DRAM2

Summary

DRAM2 (DNA damage regulated autophagy modulator 2, HGNC:28769) is a protein-coding gene on chromosome 1p13.3, encoding DNA damage-regulated autophagy modulator protein 2 (Q6UX65). Plays a role in the initiation of autophagy.

The protein encoded by this gene binds microtubule-associated protein 1 light chain 3 and is required for autophagy. Defects in this gene are a cause of retinal dystrophy. In addition, two microRNAs (microRNA 125b-1 and microRNA 144) can bind to the mRNA of this gene and produce the disease state.

Source: NCBI Gene 128338 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cone-rod dystrophy 21 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 256 total — 18 pathogenic, 13 likely-pathogenic
• GTEx eGene: eQTL in 50 tissues, sQTL in 50 (q < 0.05)
• Phenotypes (HPO): 20
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.11 (unconstrained)
• MANE Select transcript: NM_001349884

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28769
Approved symbol	DRAM2
Name	DNA damage regulated autophagy modulator 2
Location	1p13.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC54289, PRO180, WWFQ154, RP5-1180E21.1
Ensembl gene	ENSG00000156171
Ensembl biotype	protein_coding
OMIM	613360
Entrez	128338

Gene structure

Transcript identifiers

Ensembl transcripts: 119 — 65 protein_coding, 48 nonsense_mediated_decay, 6 protein_coding_CDS_not_defined

MANE Select: ENST00000484310

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 1, TSL 3: 3, TSL 5: 3

ENST00000484310, ENST00000286692, ENST00000461449, ENST00000463682, ENST00000477588, ENST00000477769, ENST00000480600, ENST00000490780, ENST00000496430, ENST00000539140, ENST00000875066, ENST00000875067, ENST00000875068, ENST00000875069, ENST00000875070, ENST00000875071, ENST00000875072, ENST00000875073, ENST00000875074, ENST00000875075, ENST00000875076, ENST00000875077, ENST00000875078, ENST00000875079, ENST00000875080, ENST00000875081, ENST00000875082, ENST00000875083, ENST00000875084, ENST00000875085, ENST00000875086, ENST00000875087, ENST00000875088, ENST00000875089, ENST00000875090, ENST00000875091, ENST00000875092, ENST00000875093, ENST00000875094, ENST00000875095, ENST00000875096, ENST00000875097, ENST00000875098, ENST00000875099, ENST00000933768, ENST00000933769, ENST00000933770, ENST00000933771, ENST00000933772, ENST00000933773, ENST00000933774, ENST00000933775, ENST00000933776, ENST00000933777, ENST00000933778, ENST00000933779, ENST00000933780, ENST00000933781, ENST00000944783, ENST00000944784, ENST00000944785, ENST00000944786, ENST00000944787, ENST00001005226, ENST00001005227, ENST00001005228, ENST00001005229, ENST00001005230, ENST00001005231, ENST00001005232, ENST00001005233, ENST00001005234, ENST00001005235, ENST00001005236, ENST00001005237, ENST00001005238, ENST00001005239, ENST00001005240, ENST00001005241, ENST00001005242, ENST00001005243, ENST00001005244, ENST00001005245, ENST00001005246, ENST00001005247, ENST00001027847, ENST00001027848, ENST00001027849, ENST00001027850, ENST00001027851, ENST00001027852, ENST00001027853, ENST00001027854, ENST00001027855, ENST00001027856, ENST00001027857, ENST00001027858, ENST00001027859, ENST00001027860, ENST00001027861, ENST00001027862, ENST00001027864, ENST00001027865, ENST00001078377, ENST00001078379, ENST00001078380, ENST00001078381, ENST00001078382, ENST00001078383, ENST00001078384, ENST00001078385, ENST00001078386, ENST00001078387, ENST00001078388, ENST00001078389, ENST00001104697, ENST00001104698, ENST00001108069, ENST00001145071

RefSeq mRNA: 13 — MANE Select: NM_001349884 NM_001349881, NM_001349882, NM_001349884, NM_001349885, NM_001349886, NM_001349887, NM_001349888, NM_001349889, NM_001349890, NM_001349891, NM_001349892, NM_001349893, NM_178454

CCDS: CCDS30801

Canonical transcript exons

ENST00000484310 — 10 exons

Exon	Start	End
ENSE00001432611	111137523	111137586
ENSE00001905298	111139501	111139666
ENSE00001908527	111140038	111140093
ENSE00003475123	111131424	111131568
ENSE00003515834	111119877	111119959
ENSE00003519402	111120516	111120693
ENSE00003555845	111118805	111118897
ENSE00003683403	111124742	111124881
ENSE00003686443	111126227	111126294
ENSE00003692470	111117163	111118267

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 97.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.8659 / max 442.4410, expressed in 1818 samples.

Highest expression (Bgee): monocyte, leukocyte, spleen, oviduct epithelium, ileal mucosa.

Genetic regulation across tissues (GTEx eQTL / sQTL)

DRAM2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 50 tissues and its splicing (sQTL) in 50 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 100 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Adipose Subcutaneous	sqtl	0.0e+00	+1.45	1:111139496:C:T
Muscle Skeletal	sqtl	4.4e-320	-1.56	1:111139496:C:T
Skin Sun Exposed Lower leg	sqtl	2.8e-289	+1.40	1:111139496:C:T
Cells Cultured fibroblasts	sqtl	2.1e-286	+1.49	1:111139496:C:T
Whole Blood	sqtl	6.8e-275	-1.54	1:111139496:C:T
Artery Tibial	sqtl	7.6e-265	+1.42	1:111139496:C:T
Adipose Visceral Omentum	sqtl	3.9e-259	-1.55	1:111139496:C:T
Thyroid	sqtl	1.7e-248	+1.40	1:111139496:C:T
Lung	sqtl	6.2e-218	-1.58	1:111139496:C:T
Skin Not Sun Exposed Suprapubic	sqtl	5.4e-217	+1.34	1:111139496:C:T
Esophagus Mucosa	sqtl	7.3e-204	-1.55	1:111139496:C:T
Colon Transverse	sqtl	2.8e-198	+1.43	1:111139496:C:T
Breast Mammary Tissue	sqtl	9.5e-194	-1.58	1:111139496:C:T
Esophagus Muscularis	sqtl	4.6e-188	+1.37	1:111139496:C:T
Nerve Tibial	sqtl	7.3e-175	-1.56	1:111139496:C:T
Artery Aorta	sqtl	7.6e-169	+1.37	1:111139496:C:T
Heart Atrial Appendage	sqtl	3.7e-161	-1.54	1:111139496:C:T
Stomach	sqtl	2.9e-150	+1.44	1:111139496:C:T
Colon Sigmoid	sqtl	2.7e-149	-1.53	1:111139496:C:T
Esophagus Gastroesophageal Junction	sqtl	1.3e-127	+1.46	1:111139496:C:T

FANTOM5 promoters

7 alternative TSS:

Promoter ID	TPM avg	Samples expressed
13796	28.9718	1810
13798	2.8340	1425
13797	2.0188	1272
13799	1.5339	907
13793	0.7321	203
13795	0.5397	247
13794	0.2357	30

Top tissues by expression

showing 100 of 261 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	97.53	gold quality
leukocyte	CL:0000738	97.44	gold quality
spleen	UBERON:0002106	97.43	gold quality
oviduct epithelium	UBERON:0004804	97.25	gold quality
ileal mucosa	UBERON:0000331	96.77	gold quality
right uterine tube	UBERON:0001302	96.66	gold quality
vermiform appendix	UBERON:0001154	96.60	gold quality
gall bladder	UBERON:0002110	96.57	gold quality
lymph node	UBERON:0000029	96.40	gold quality
granulocyte	CL:0000094	96.38	gold quality
rectum	UBERON:0001052	95.99	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.91	gold quality
mucosa of stomach	UBERON:0001199	94.99	gold quality
subcutaneous adipose tissue	UBERON:0002190	94.96	gold quality
omental fat pad	UBERON:0010414	94.92	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.91	gold quality
peritoneum	UBERON:0002358	94.88	gold quality
cartilage tissue	UBERON:0002418	94.75	gold quality
adipose tissue	UBERON:0001013	94.72	gold quality
right lung	UBERON:0002167	94.61	gold quality
minor salivary gland	UBERON:0001830	94.59	gold quality
body of pancreas	UBERON:0001150	94.41	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.29	gold quality
small intestine	UBERON:0002108	94.27	gold quality
fallopian tube	UBERON:0003889	94.23	gold quality
transverse colon	UBERON:0001157	94.16	gold quality
bronchial epithelial cell	CL:0002328	93.89	gold quality
mucosa of transverse colon	UBERON:0004991	93.85	gold quality
cerebellar hemisphere	UBERON:0002245	93.84	gold quality
upper lobe of left lung	UBERON:0008952	93.77	gold quality
cerebellar cortex	UBERON:0002129	93.70	gold quality
right coronary artery	UBERON:0001625	93.66	gold quality
intestine	UBERON:0000160	93.63	gold quality
right adrenal gland cortex	UBERON:0035827	93.53	gold quality
descending thoracic aorta	UBERON:0002345	93.50	gold quality
upper lobe of lung	UBERON:0008948	93.48	gold quality
cardiac muscle of right atrium	UBERON:0003379	93.45	gold quality
right ovary	UBERON:0002118	93.42	gold quality
large intestine	UBERON:0000059	93.41	gold quality
smooth muscle tissue	UBERON:0001135	93.41	gold quality
left ovary	UBERON:0002119	93.41	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.41	gold quality
colon	UBERON:0001155	93.40	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.39	gold quality
body of stomach	UBERON:0001161	93.36	gold quality
left adrenal gland	UBERON:0001234	93.29	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.29	gold quality
endocervix	UBERON:0000458	93.25	gold quality
pancreas	UBERON:0001264	93.25	gold quality
bronchus	UBERON:0002185	93.24	gold quality
skin of leg	UBERON:0001511	93.21	gold quality
mouth mucosa	UBERON:0003729	93.18	gold quality
right adrenal gland	UBERON:0001233	93.14	gold quality
skin of abdomen	UBERON:0001416	93.14	gold quality
islet of Langerhans	UBERON:0000006	93.10	gold quality
stromal cell of endometrium	CL:0002255	93.02	gold quality
metanephros cortex	UBERON:0010533	93.01	gold quality
left adrenal gland cortex	UBERON:0035825	92.95	gold quality
saliva-secreting gland	UBERON:0001044	92.94	gold quality
epithelium of nasopharynx	UBERON:0001951	92.86	gold quality
left coronary artery	UBERON:0001626	92.85	gold quality
nasopharynx	UBERON:0001728	92.85	gold quality
cerebellum	UBERON:0002037	92.79	gold quality
body of uterus	UBERON:0009853	92.77	gold quality
ovary	UBERON:0000992	92.76	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	92.76	gold quality
tibial nerve	UBERON:0001323	92.75	gold quality
duodenum	UBERON:0002114	92.70	gold quality
vagina	UBERON:0000996	92.62	gold quality
left ventricle myocardium	UBERON:0006566	92.49	gold quality
zone of skin	UBERON:0000014	92.41	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.30	gold quality
tibial artery	UBERON:0007610	92.16	gold quality
popliteal artery	UBERON:0002250	92.15	gold quality
adrenal gland	UBERON:0002369	92.13	gold quality
thoracic aorta	UBERON:0001515	92.11	gold quality
artery	UBERON:0001637	92.11	gold quality
ectocervix	UBERON:0012249	92.10	gold quality
ascending aorta	UBERON:0001496	92.07	gold quality
blood	UBERON:0000178	92.04	gold quality
aorta	UBERON:0000947	92.03	gold quality
right atrium auricular region	UBERON:0006631	91.91	gold quality
ventricular zone	UBERON:0003053	91.89	gold quality
upper arm skin	UBERON:0004263	91.88	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	91.86	gold quality
jejunal mucosa	UBERON:0000399	91.85	gold quality
adrenal cortex	UBERON:0001235	91.81	gold quality
left lobe of thyroid gland	UBERON:0001120	91.80	gold quality
lower esophagus	UBERON:0013473	91.80	gold quality
coronary artery	UBERON:0001621	91.79	gold quality
lower esophagus muscularis layer	UBERON:0035833	91.79	gold quality
right lobe of thyroid gland	UBERON:0001119	91.75	gold quality
lung	UBERON:0002048	91.74	gold quality
adrenal tissue	UBERON:0018303	91.74	gold quality
caecum	UBERON:0001153	91.71	gold quality
stomach	UBERON:0000945	91.66	gold quality
metanephros	UBERON:0000081	91.63	gold quality
superficial temporal artery	UBERON:0001614	91.63	gold quality
left uterine tube	UBERON:0001303	91.62	gold quality
cardiac atrium	UBERON:0002081	91.61	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6379	no	1496.64
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Lymph node	tissue	51.7	high
Tonsil	tissue	47.1	high
Spleen	tissue	42.5	high
Placenta	tissue	38.6	high
Adipose tissue	tissue	35.5	not detected
Gallbladder	tissue	34.0	medium
Hippocampal formation	tissue	31.7
Appendix	tissue	31.0	high
Rectum	tissue	28.8	high
Choroid plexus	tissue	28.4
Corpus callosum	tissue	28.3
Fallopian tube	tissue	28.3	high
Urinary bladder	tissue	27.5	high
Duodenum	tissue	26.9	high
Parathyroid gland	tissue	26.6	medium
Thymus	tissue	25.9
Breast	tissue	25.1	medium
Colon	tissue	25.0	high
Small intestine	tissue	24.7	medium
Kidney	tissue	24.7	medium
Salivary gland	tissue	24.3	low
Pancreas	tissue	24.0	medium
Caudate putamen	tissue	23.7
Lung	tissue	23.5	medium
Ovary	tissue	23.4	low
Liver	tissue	23.2	medium
Heart muscle	tissue	22.2	medium
Putamen	tissue	22.2
Stomach 1	tissue	22.1	medium
Tongue	tissue	22.1
Cervix	tissue	21.8	medium
Adrenal gland	tissue	21.8	high
Spinal cord	tissue	21.7
Medulla oblongata	tissue	21.3
Thyroid gland	tissue	20.5	medium
Midbrain	tissue	20.1
Pons	tissue	19.7
Substantia nigra	tissue	19.5
Frontal cortex	tissue	19.3
Thalamus	tissue	19.2
Cerebellum	tissue	19.2	high
Olfactory bulb	tissue	18.1
Superior colliculi	tissue	17.8
Hypothalamus	tissue	17.6
Septum	tissue	17.5
Periaqueductal gray	tissue	17.4
Skin 1	tissue	16.9	high
Bone marrow	tissue	16.9	not detected
Prostate	tissue	16.7	high
Endometrium 1	tissue	16.6	low
Epididymis	tissue	16.6	low
Ventral forebrain	tissue	16.5
Cerebral cortex	tissue	16.4	low
Occipital cortex	tissue	16.4
Smooth muscle	tissue	15.8	not detected
Seminal vesicle	tissue	15.7	low
Retina	tissue	15.6
Vagina	tissue	15.6	medium
Skeletal muscle	tissue	15.2	medium
Somatosensory cortex	tissue	15.1

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Dorsal hippocampus (31.7), White matter (28.3), Ventral hippocampus (22.4), Ventral spinal cord (21.7), Dorsal spinal cord (20.9).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

7 targets:

Target	Regulation
CDKN1A	Repression
RAC1	Activation
RHOA	Activation
RHOB	Repression
RHOC	Activation
ROCK1	Activation
TP53	Repression

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

Targeting DRAM2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 75 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514

Functional genomics

gnomAD constraint: pLI 1.06e-06, LOEUF 1.11, missense Z 0.397 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000484310 — one region, missense o/e 0.98.

Literature-anchored findings (GeneRIF, showing 10)

• DRAM2 is different from DRAM as it not induced by p53 or p73. DRAM2 is also a lysosomal protein, its overexpression does not modulate autophagy. (PMID:19556885)
• reduced expression of DRAM2 may contribute to enhanced cell survival in tumor cells. (PMID:19895784)
• The expression of damage-regulated autophagy modulator 2 (DRAM2) contributes to autophagy induction. (PMID:21584698)
• Biallelic mutations in the autophagy regulator DRAM2 cause retinal dystrophy with early macular involvement. (PMID:25983245)
• Genetic variants on chromosome 1p13.3 near the damage-regulated autophagy modulator 2 gene DRAM2 associated with Non-ST Elevation Myocardial Infarction (rs656843; odds ratio 1.57, P = 3.11 x 10(-10)) in the case-control analysis. (PMID:26509668)
• Recessive variants in DRAM2, an autophagy regulator gene, have been recently identified as a cause of retinal dystrophy with early macular involvement (PMID:26720460)
• Mycobacterium tuberculosis significantly induces the expression of MIR144*/hsa-miR-144-5p, which targets the 3’-untranslated region of DRAM2. (PMID:27764573)
• Three novel homozygous mutations in the autophagy gene DRAM2 were identified as the molecular cause of disease in the three families: c.518-1G>A, c.628_629insAG and c.693+2T>A. (PMID:31394102)
• Clinical Course and Electron Microscopic Findings in Lymphocytes of Patients with DRAM2-Associated Retinopathy. (PMID:32079136)
• The Clinical Spectrum and Disease Course of DRAM2 Retinopathy. (PMID:35806404)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	dram2a	ENSDARG00000043569
danio_rerio	dram2b	ENSDARG00000044241
mus_musculus	Dram2	ENSMUSG00000027900
rattus_norvegicus	Dram2	ENSRNOG00000017744
drosophila_melanogaster	CG4025	FBGN0025624
caenorhabditis_elegans		WBGENE00007878

Paralogs (4): DRAM1 (ENSG00000136048), TMEM150A (ENSG00000168890), TMEM150B (ENSG00000180061), TMEM150C (ENSG00000249242)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1914421) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 6 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal coat/hair pigmentation	1
increased susceptibility to injury	1
abnormal eye physiology	1
retina cone cell degeneration	1
retina photoreceptor degeneration	1
decreased total retina thickness	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	A5D7C9	98.0%	Diamond
Xenopus tropicalis	Q28BP2	97.4%	Diamond
Xenopus laevis	Q6GPL4	97.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CEPT1	protein-coding	10390
LRIF1	protein-coding	55791
CD53	protein-coding	963
DENND2D	protein-coding	79961
CHI3L2	protein-coding	1117

Protein

Protein identifiers

DNA damage-regulated autophagy modulator protein 2 — Q6UX65 (reviewed: Q6UX65)

Alternative names: Transmembrane protein 77

All UniProt accessions (2): Q6UX65, S4R2Z2

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in the initiation of autophagy. In the retina, might be involved in the process of photoreceptor cells renewal and recycling to preserve visual function. Induces apoptotic cell death when coexpressed with DRAM1.

Subcellular location. Lysosome membrane. Photoreceptor inner segment. Apical cell membrane.

Tissue specificity. Expression is down-regulated in ovarian tumors (at protein level). Widely expressed with highest levels in placenta and heart. Expressed in the retina. Not detected in brain or thymus.

Disease relevance. Cone-rod dystrophy 21 (CORD21) [MIM:616502] A form of cone-rod dystrophy, an inherited retinal dystrophy characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors. The disease is caused by variants affecting the gene represented in this entry.

Induction. Not induced by p53/TP53 or TP73/p73.

Similarity. Belongs to the DRAM/TMEM150 family.

RefSeq proteins (13): NP_001336810, NP_001336811, NP_001336813, NP_001336814, NP_001336815, NP_001336816, NP_001336817, NP_001336818, NP_001336819, NP_001336820, NP_001336821, NP_001336822, NP_848549 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019402	CWH43_N	Domain
IPR050911	DRAM/TMEM150_Autophagy_Mod	Family

Pfam: PF10277

UniProt features (13 total): transmembrane region 6, sequence variant 5, chain 1, sequence conflict 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UX65-F1	91.35	0.75

Human Protein Atlas

Protein class: Transporters, Accessory Factors Involved in Transport, Predicted membrane proteins, Disease related genes, Potential drug targets, Human disease related genes, Eye disease

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): golgi apparatus; vesicles

Antibody reliability (HPA): IH supported · IF enhanced

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 201 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, GOCC_VACUOLAR_MEMBRANE, AAGCCAT_MIR135A_MIR135B, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, TGACCTY_ERR1_Q2, MARTINEZ_RB1_TARGETS_UP, GOBP_REGULATION_OF_CATABOLIC_PROCESS, CHARAFE_BREAST_CANCER_BASAL_VS_MESENCHYMAL_UP, GOBP_PHOTORECEPTOR_CELL_MAINTENANCE, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_6, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_DN, GOCC_APICAL_PLASMA_MEMBRANE

GO Biological Process (5): autophagy (GO:0006914), apoptotic process (GO:0006915), visual perception (GO:0007601), regulation of autophagy (GO:0010506), photoreceptor cell maintenance (GO:0045494)

GO Cellular Component (7): photoreceptor inner segment (GO:0001917), cytoplasm (GO:0005737), lysosome (GO:0005764), lysosomal membrane (GO:0005765), Golgi apparatus (GO:0005794), apical plasma membrane (GO:0016324), endomembrane system (GO:0012505)

GO top-level categories

23 GO namespaces:

Category	Terms
cellular anatomical structure	3
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
sensory perception of light stimulus	1
autophagy	1
regulation of catabolic process	1
retina homeostasis	1
multicellular organismal process	1
intracellular anatomical structure	1
lytic vacuole	1
lysosome	1
lytic vacuole membrane	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
apical part of cell	1
plasma membrane region	1
vacuole	1
plasma membrane	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 6 of 12 annotations. The rest are phylogenetic / computational / electronic (IEA).

6 experimentally-supported GO terms:

GO term	NS	Evidence
photoreceptor cell maintenance	BP	mutant phenotype
regulation of autophagy	BP	direct assay
visual perception	BP	mutant phenotype
Golgi apparatus	CC	direct assay
cytoplasm	CC	direct assay
lysosome	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 532 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DRAM2	CFAP418	Q96NL8	489
DRAM2	TTLL5	Q6EMB2	460
DRAM2	TP53	P04637	458
DRAM2	POC1B	Q8TC44	448
DRAM2	PITPNM3	Q9BZ71	428
DRAM2	THYN1	Q9P016	427
DRAM2	RAB28	P51157	402
DRAM2	RAX2	Q96IS3	401
DRAM2	ATG4C	Q96DT6	397
DRAM2	SIPA1L1	O43166	370
DRAM2	UVRAG	Q9P2Y5	370
DRAM2	ULK1	O75385	366
DRAM2	TTC12	Q9H892	365
DRAM2	RIMS1	Q86UR5	364
DRAM2	SPG7	Q9UQ90	362

IntAct

BioGRID (10 interactions; top human partners by supporting records): AGO2 (Affinity Capture-RNA), CSK (Synthetic Lethality), ELAVL1 (Affinity Capture-RNA), LAMP1 (Affinity Capture-MS), SLC19A2 (Affinity Capture-MS), SLC35F1 (Affinity Capture-MS), SLC6A12 (Affinity Capture-MS)

SIGNOR signaling

8 signaling interactions:

A	Effect	B	Mechanism
DRAM2	“up-regulates quantity by expression”	RAC1	“transcriptional regulation”
DRAM2	“up-regulates quantity by expression”	RHOA	“transcriptional regulation”
DRAM2	“up-regulates quantity by expression”	RHOC	“transcriptional regulation”
DRAM2	“up-regulates quantity by expression”	ROCK1	“transcriptional regulation”
DRAM2	“down-regulates quantity by repression”	RHOB	“transcriptional regulation”
DRAM2	“down-regulates quantity by repression”	TP53	“transcriptional regulation”
DRAM2	“down-regulates quantity by repression”	CDKN1A	“transcriptional regulation”
TP53	“down-regulates quantity by repression”	DRAM2	“transcriptional regulation”

Disease & clinical

Genetic variants

Variant evidence for DRAM2: 256 ClinVar records (31 pathogenic / likely pathogenic); 3 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

256 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	13
Uncertain significance	118
Likely benign	81
Benign	4

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 31 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
192239	NM_001349884.2(DRAM2):c.494G>A (p.Trp165Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
192233	NM_001349884.2(DRAM2):c.140del (p.Gly47fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
1322768	NM_001349884.2(DRAM2):c.80dup (p.Tyr27Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1518344	NM_001349884.2(DRAM2):c.200-2_211del	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
2093364	NM_001349884.2(DRAM2):c.601-1G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
3718574	NM_001349884.2(DRAM2):c.518-1G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
192237	NM_001349884.2(DRAM2):c.362A>T (p.His121Leu)	Pathogenic	criteria provided, single submitter	2
192238	NM_001349884.2(DRAM2):c.131G>A (p.Ser44Asn)	Pathogenic	criteria provided, single submitter	2
192235	NM_001349884.2(DRAM2):c.79T>C (p.Tyr27His)	Pathogenic	criteria provided, single submitter	1
192236	NM_001349884.2(DRAM2):c.217_225del (p.Val73_Tyr75del)	Pathogenic	criteria provided, single submitter	1
1074281	NM_001349884.2(DRAM2):c.92dup (p.Thr32fs)	Pathogenic	criteria provided, single submitter	1
1367200	NM_001349884.2(DRAM2):c.3G>A (p.Met1Ile)	Pathogenic	criteria provided, single submitter	1
1369252	NM_001349884.2(DRAM2):c.5G>A (p.Trp2Ter)	Pathogenic	criteria provided, single submitter	1
1396222	NM_001349884.2(DRAM2):c.678C>A (p.Tyr226Ter)	Pathogenic	criteria provided, single submitter	1
1453413	NM_001349884.2(DRAM2):c.638G>A (p.Trp213Ter)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore DRAM2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 25 predictions of 1,116):

Position(s)	Effect	Δscore	Sites
1:111118803–111118804	donor_loss	1.0000	5
1:111131423	donor_loss	1.0000	2
1:111118803	donor_loss	0.9900
1:111118905	acceptor_gain	0.9900
1:111119962	acceptor_gain	0.9900
1:111131422	donor_loss	0.9900	2
1:111131569–111131570	acceptor_loss	0.9900	6
1:111139519	donor_gain	0.9900
1:111139540	donor_gain	0.9900
1:111140036–111140037	donor_loss	0.9900	5

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	2.86e-06
Colon Adenocarcinoma (TCGA)	favorable	0.000158

Disease associations

OMIM: gene MIM:613360 | disease phenotypes: MIM:616502

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
cone-rod dystrophy 21	Strong	Autosomal recessive	3
cone-rod dystrophy	Supportive	Autosomal dominant

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (1 panels, 1 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

1 panels:

Panel	Rating
Retinal disorders	green

Mondo (4): cone-rod dystrophy 21 (MONDO:0014669), inherited retinal dystrophy (MONDO:0019118), retinal disorder (MONDO:0005283), cone-rod dystrophy (MONDO:0015993)

Orphanet (2): Cone rod dystrophy (Orphanet:1872), OBSOLETE: Inherited retinal disorder (Orphanet:71862)

HPO phenotypes

20 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000505	Visual impairment
HP:0000529	Progressive visual loss
HP:0000543	Optic disc pallor
HP:0000551	Color vision defect
HP:0000556	Retinal dystrophy
HP:0000603	Central scotoma
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000662	Nyctalopia
HP:0001105	Retinal atrophy
HP:0007401	Macular atrophy
HP:0007641	Dyschromatopsia
HP:0007663	Reduced visual acuity
HP:0007703	Abnormal retinal pigmentation
HP:0007737	Spicular pigmentation of the retina
HP:0007843	Attenuation of retinal blood vessels
HP:0011462	Young adult onset
HP:0012508	Metamorphopsia
HP:0030466	Abnormal full-field electroretinogram

GWAS associations

3 associations:

Study	Trait	p-value
GCST90002397_253	Mean spheric corpuscular volume	1e-14
GCST90002396_214	Mean reticulocyte volume	4e-14
GCST007998_7	Intraocular pressure	1e-8

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors

3 disease descriptors:

Descriptor	Name	Tree numbers
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression	9
methylmercuric chloride	decreases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
sodium arsenite	increases expression, affects cotreatment, increases abundance	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
sulphoraphene	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
Temozolomide	decreases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Atrazine	decreases expression	1
Cisplatin	decreases response to substance, increases expression	1
Dexamethasone	increases expression, affects cotreatment	1
Indomethacin	affects cotreatment, increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 79 trials:

NCT	Phase	Status	Title
NCT01955135	Phase 4	COMPLETED	Anesthesia for Retinopathy of Prematurity
NCT07685886	Phase 4	NOT_YET_RECRUITING	MIRACLE-T2D Montelukast Intervention for Renal, Cardiovascular and Eye Health in Type 2 Diabetes
NCT04224207	Phase 3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	Phase 3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT01773278	Phase 2	UNKNOWN	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT03763227	Phase 2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	Phase 2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	Phase 2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT01373476	Phase 2	COMPLETED	Multicentre, Randomized, Controlled Trial of Qideng Mingmu Capsule in The Treatment of Diabetic Retinopathy
NCT01793090	Phase 2	COMPLETED	EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment
NCT05902962	Phase 1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	Phase 1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	Phase 1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT06467344	Phase 1/2	RECRUITING	Study to Evaluate ACDN-01 in ABCA4-related Stargardt Retinopathy (STELLAR)
NCT06789445	Phase 1/2	RECRUITING	A Study to Investigate the Safety of OpCT-001 in Adults Who Have Primary Photoreceptor Disease (CLARICO)
NCT00427180	Not specified	UNKNOWN	IRIS PILOT - Extended Pilot Study With a Retinal Implant System
NCT01864486	Not specified	COMPLETED	Restoring Vision With the Intelligent Retinal Implant System (IRIS V1)in Patients With Retinal Dystrophy
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT02670980	Not specified	COMPLETED	Compensation for Blindness With the Intelligent Retinal Implant System (IRIS V2) in Patients With Retinal Dystrophy
NCT04658251	Not specified	TERMINATED	Study of New Mutations in Cone Disorders
NCT05355415	Not specified	RECRUITING	Adaptive Optics Imaging of Outer Retinal Diseases
NCT06445322	Not specified	RECRUITING	Prescreening Study to Identify Potential Stargardt Participants for ACDN-01 Clinical Trials (STARPATH)
NCT07548944	Not specified	RECRUITING	Observational Study to Investigate the Short-term Effects of Transcorneal Electrical Stimulation on Visual Performance
NCT04855045	Phase 2/3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT03872479	Phase 1/2	UNKNOWN	Single Ascending Dose Study in Participants With LCA10
NCT04123626	Phase 1/2	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety and Tolerability of QR-1123 in Subjects With Autosomal Dominant Retinitis Pigmentosa Due to the P23H Mutation in the RHO Gene
NCT04545736	Phase 1/2	ACTIVE_NOT_RECRUITING	Oral Metformin for Treatment of ABCA4 Retinopathy
NCT06212297	Phase 1/2	ACTIVE_NOT_RECRUITING	Fellow-eye Study (FE) of LX101 in Subjects With Inherited Retinal Dystrophy
NCT06852963	Phase 1/2	ACTIVE_NOT_RECRUITING	A Repeat-Dose, Open-Label, Two Arm Safety and Efficacy Study of Two Doses of VP-001 Administered Intravitreally in Participants With Confirmed PRPF31 Mutation-Associated Retinal Dystrophy, Including Participants Previously Treated With VP001
NCT07177196	Phase 1/2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide Therapy for a Single Participant With PRPH2 Mutation Associated With Retinal Dystrophy
NCT07063030	Early Phase 1	RECRUITING	A Study of LX107 Gene Therapy in AIPL1-IRD Patients
NCT07656753	Early Phase 1	RECRUITING	Safety and Efficacy Study of PUMCH-E111 Injection in Subjects With RLBP1 Related Inherited Retinal Dystrophy
NCT01546181	Not specified	COMPLETED	Retinal Imaging by Adaptive Optics in Healthy Eyes and During Retinal and General Diseases
NCT01876147	Not specified	COMPLETED	Visual and Functional Assessment in Low Vision Patients
NCT01920867	Not specified	UNKNOWN	Stem Cell Ophthalmology Treatment Study
NCT02014389	Not specified	RECRUITING	Evaluation of Objective Perimetry Using Chromatic Multifocal Pupillometer
NCT02983305	Not specified	COMPLETED	Optical Head-Mounted Display Technology for Low Vision Rehabilitation
NCT03592017	Not specified	COMPLETED	Performance of Long-wavelength Autofluorescence Imaging
NCT03662386	Not specified	TERMINATED	Prospective Analysis of Genotype-phenotype Correlations Observed in a Large Cohort of Patients With Hereditary Retinal Dystrophies - GEPHIRD
NCT03691168	Not specified	UNKNOWN	Multi-center Observation of the Natural Course of Inherited Retinal Dystrophies
NCT03843840	Not specified	COMPLETED	Dual Wavelength OCT
NCT03853252	Not specified	COMPLETED	iPS Cells of Patients for Models of Retinal Dystrophies
NCT05130385	Not specified	UNKNOWN	High Resolution Optical Coherence Tomography
NCT05294978	Not specified	RECRUITING	EyeConic: Qualification for Cone-Optogenetics
NCT05573984	Not specified	ACTIVE_NOT_RECRUITING	Natural History of PRPF31 Mutation-Associated Retinal Dystrophy
NCT05793515	Not specified	COMPLETED	Mechanisms of Inherited Retinal Dystrophies Using Whole Genome Sequencing and in Vitro and in Vivo Models
NCT05820100	Not specified	COMPLETED	Observational Study to Assess the Reliability and Validity of the MLYMT and MLSDT
NCT05976139	Not specified	RECRUITING	Micropulsed Laser in Patients With Macular Oedema in Retinal Dystrophies
NCT06162585	Not specified	ACTIVE_NOT_RECRUITING	Non-Interventional Long Term Follow-up Study of Participants Previously Enrolled in the RESTORE Study
NCT06177977	Not specified	RECRUITING	SS-HH-OCT as a Novel Diagnostic Modality for Early-Onset Retinal Dystrophies (EORDs)
NCT06375239	Not specified	RECRUITING	Observational Study to Assess Endpoint Operational Feasibility & Measurement Properties in Patients with Retinal Degeneration
NCT06908161	Not specified	NOT_YET_RECRUITING	Functional Assessments in Vision Impairment
NCT07085533	Not specified	RECRUITING	Natural History Study of Inherited Retinal Diseases
NCT07502664	Not specified	RECRUITING	Development and Evaluation of Functional Visual Field and Navigation Endpoints in Moderate to Profound Inherited Retinal Disease (DEFINE-IRD)
NCT07529041	Not specified	ENROLLING_BY_INVITATION	Real-time Acoustic Biofeedback for Enhancing Fixation Stability: A Proof-of-concept Study to Improve Ophthalmic Imaging Diagnostic Quality
NCT04311112	Phase 2/3	WITHDRAWN	Safety and Efficacy of Zuretinol Acetate in Subjects With Inherited Retinal Disease
NCT04008121	Early Phase 1	RECRUITING	Feasibility and Safety of MB-102 in Ocular Angiography as Compared to Fluorescein Sodium
NCT00259701	Not specified	COMPLETED	Microvascular Reactivity.
NCT00331370	Not specified	UNKNOWN	Hypertension Related Damage to the Microcirculation in South Asian: Emergence, Predictive Power and Reversibility
NCT00618644	Not specified	WITHDRAWN	Ranibizumab for Neovascularization in Sickle Cell Retinopathy