DHDDS

Summary

DHDDS (dehydrodolichyl diphosphate synthase subunit, HGNC:20603) is a protein-coding gene on chromosome 1p36.11, encoding Dehydrodolichyl diphosphate synthase complex subunit DHDDS (Q86SQ9). With NUS1, forms the dehydrodolichyl diphosphate synthase (DDS) complex, an essential component of the dolichol monophosphate (Dol-P) biosynthetic machinery. It is a common-essential gene (DepMap: required in 99.6% of cancer cell lines).

The protein encoded by this gene catalyzes cis-prenyl chain elongation to produce the polyprenyl backbone of dolichol, a glycosyl carrier lipid required for the biosynthesis of several classes of glycoproteins. Mutations in this gene are associated with retinitis pigmentosa type 59. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 79947 — RefSeq curated summary.

At a glance

• Gene–disease (curated): DHDDS-CDG (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 639 total — 17 pathogenic, 24 likely-pathogenic
• Phenotypes (HPO): 97
• Cancer dependency (DepMap): dependent in 99.6% of screened cell lines (common-essential)
• MANE Select transcript: NM_205861

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20603
Approved symbol	DHDDS
Name	dehydrodolichyl diphosphate synthase subunit
Location	1p36.11
Locus type	gene with protein product
Status	Approved
Aliases	HDS, FLJ13102, DS, RP59, hCIT
Ensembl gene	ENSG00000117682
Ensembl biotype	protein_coding
OMIM	608172
Entrez	79947

Gene structure

Transcript identifiers

Ensembl transcripts: 55 — 42 protein_coding, 7 retained_intron, 5 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000236342, ENST00000360009, ENST00000374185, ENST00000374186, ENST00000416052, ENST00000427245, ENST00000430232, ENST00000431933, ENST00000434391, ENST00000436153, ENST00000487944, ENST00000525165, ENST00000525326, ENST00000525410, ENST00000525546, ENST00000525682, ENST00000526219, ENST00000526278, ENST00000527611, ENST00000528557, ENST00000529688, ENST00000530781, ENST00000531312, ENST00000531955, ENST00000533087, ENST00000703198, ENST00000703199, ENST00000703200, ENST00000703201, ENST00000703202, ENST00000703203, ENST00000703262, ENST00000703263, ENST00000703264, ENST00000881464, ENST00000881465, ENST00000881466, ENST00000881467, ENST00000881468, ENST00000881469, ENST00000881470, ENST00000881471, ENST00000881472, ENST00000881473, ENST00000881474, ENST00000919035, ENST00000919036, ENST00000919037, ENST00000919038, ENST00000919039, ENST00000961105, ENST00000961106, ENST00000961107, ENST00000961108, ENST00000961109

RefSeq mRNA: 5 — MANE Select: NM_205861 NM_001243564, NM_001243565, NM_001319959, NM_024887, NM_205861

CCDS: CCDS281, CCDS282, CCDS57983, CCDS57984

Canonical transcript exons

ENST00000236342 — 9 exons

Exon	Start	End
ENSE00001691018	26468895	26471306
ENSE00001781551	26442731	26442873
ENSE00003571564	26457791	26457905
ENSE00003617490	26446316	26446432
ENSE00003670616	26432891	26433008
ENSE00003678060	26447559	26447660
ENSE00003786864	26438168	26438284
ENSE00003790149	26460037	26460144
ENSE00003847307	26432321	26432376

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 98.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.8765 / max 301.4259, expressed in 1811 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1617	12.3134	1792
1618	7.5541	1754
1619	0.0090	3

Top tissues by expression

283 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	98.57	gold quality
cerebellar cortex	UBERON:0002129	97.10	gold quality
cerebellar hemisphere	UBERON:0002245	97.10	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.85	gold quality
male germ cell	CL:0000015	96.53	gold quality
cerebellum	UBERON:0002037	96.15	gold quality
rectum	UBERON:0001052	94.49	gold quality
tendon of biceps brachii	UBERON:0008188	93.13	gold quality
mucosa of transverse colon	UBERON:0004991	92.02	gold quality
transverse colon	UBERON:0001157	91.60	gold quality
islet of Langerhans	UBERON:0000006	91.50	gold quality
cerebellar vermis	UBERON:0004720	91.32	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.30	gold quality
adipose tissue	UBERON:0001013	91.28	gold quality
colonic epithelium	UBERON:0000397	90.87	gold quality
connective tissue	UBERON:0002384	90.71	gold quality
sural nerve	UBERON:0015488	90.59	gold quality
stromal cell of endometrium	CL:0002255	90.18	gold quality
esophagus mucosa	UBERON:0002469	89.82	gold quality
skin of leg	UBERON:0001511	89.77	gold quality
adipose tissue of abdominal region	UBERON:0007808	89.39	gold quality
adrenal tissue	UBERON:0018303	89.38	gold quality
parotid gland	UBERON:0001831	89.27	silver quality
saliva-secreting gland	UBERON:0001044	89.24	gold quality
apex of heart	UBERON:0002098	89.19	gold quality
omental fat pad	UBERON:0010414	89.14	gold quality
peritoneum	UBERON:0002358	89.12	gold quality
adenohypophysis	UBERON:0002196	89.11	gold quality
skin of abdomen	UBERON:0001416	88.98	gold quality
metanephros cortex	UBERON:0010533	88.89	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.86

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF3, FOS, JUN

miRNA regulators (miRDB)

68 targeting DHDDS, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-122B-5P	99.46	70.81	1457
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-6731-5P	99.28	67.42	2375

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.6% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 15)

• identification and amino acid sequence expressed in yeast (PMID:12591616)
• identification and characterization; overexpression of CIT in CHO cells results in a modest increase in cis-isoprenyltransferase activity associated with microsomal fractions (PMID:14652022)
• molecular cloning; results suggest a regulatory relationship between CPT activity and dolichol biosynthesis, and may implicate CPT in the levels of dolichol-oligosaccharide intermediate biosynthesis (PMID:15850770)
• A missense mutation in DHDDS is associated with autosomal-recessive retinitis pigmentosa. (PMID:21295282)
• A variant in DHDDS is associated with retinitis pigmentosa. (PMID:21295283)
• A single-nucleotide mutation in the gene that encodes DHDDS has been identified by whole exome sequencing as the cause of the non-syndromic recessive retinitis pigmentosa (RP) in a family of Ashkenazi Jewish origin. (PMID:24664694)
• We identified the MAK and DHDDS mutations homozygously in only 2.1% and 0.8%, respectively, of patients of mixed ethnicity, but in 25.7% and 8.6%, respectively, of cases reporting Jewish ancestry (PMID:25255364)
• Study describe a patient presenting with severe multisystem disease associated with DHDDS deficiency. As retinitis pigmentosa is the only clinical sign in previously reported cases, this report broadens the spectrum of phenotypes associated with this condition. (PMID:27343064)
• findings show that eukaryotic cis-PT is composed of the NgBR and hCIT subunits. The strong conservation of the RXG motif among NgBR orthologs indicates that this subunit is critical for the synthesis of polyprenol diphosphates and cellular function. (PMID:28842490)
• The clinical data show that in general, patients with biallelic MAK mutations had a later age of onset and a milder retinal phenotype compared with patients with biallelic DHDDS mutations. (PMID:29276052)
• Structural Characterization of Full-Length Human Dehydrodolichyl Diphosphate Synthase Using an Integrative Computational and Experimental Approach. (PMID:31661879)
• HOXB4 promotes the malignant progression of ovarian cancer via DHDDS. (PMID:32178630)
• Structural elucidation of the cis-prenyltransferase NgBR/DHDDS complex reveals insights in regulation of protein glycosylation. (PMID:32817466)
• Structural basis of heterotetrameric assembly and disease mutations in the human cis-prenyltransferase complex. (PMID:33077723)
• Phenotype of heterozygous variants of dehydrodolichol diphosphate synthase. (PMID:34275143)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dhdds	ENSDARG00000039851
mus_musculus	Dhdds	ENSMUSG00000012117
rattus_norvegicus	Dhdds	ENSRNOG00000014665
drosophila_melanogaster	Dhdds	FBGN0029980
caenorhabditis_elegans		WBGENE00044025

Protein

Protein identifiers

Dehydrodolichyl diphosphate synthase complex subunit DHDDS — Q86SQ9 (reviewed: Q86SQ9)

Alternative names: Cis-isoprenyltransferase, Cis-prenyltransferase subunit hCIT, Epididymis tissue protein Li 189m

All UniProt accessions (21): A0A8V8TQ81, A0A8V8TQ96, A0A8V8TQQ9, A0A8V8TQS0, A0A8V8TQU2, A0A8V8TR89, A0A8V8TRI4, Q86SQ9, E9PI09, E9PI64, E9PKJ5, E9PL99, E9PR24, E9PRS7, E9PSH7, H0Y4T1, Q5T0A0, Q5T0A1, Q5T0A2, Q5T0A3, Q5T0A6

UniProt curated annotations — full annotation on UniProt →

Function. With NUS1, forms the dehydrodolichyl diphosphate synthase (DDS) complex, an essential component of the dolichol monophosphate (Dol-P) biosynthetic machinery. Both subunits contribute to enzymatic activity, i.e. condensation of multiple copies of isopentenyl pyrophosphate (IPP) to farnesyl pyrophosphate (FPP) to produce dehydrodolichyl diphosphate (Dedol-PP), a precursor of dolichol phosphate which is utilized as a sugar carrier in protein glycosylation in the endoplasmic reticulum (ER). Synthesizes long-chain polyprenols, mostly of C95 and C100 chain length. Regulates the glycosylation and stability of nascent NPC2, thereby promoting trafficking of LDL-derived cholesterol.

Subunit / interactions. The active dehydrodolichyl diphosphate synthase complex is a heterotetramer composed of a dimer of heterodimer of DHDDS and NUS1. Interacts with NPC2.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Ubiquitous. Expressed at high levels in testis and kidney. Expressed in epididymis (at protein level).

Disease relevance. Retinitis pigmentosa 59 (RP59) [MIM:613861] A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. The disease is caused by variants affecting the gene represented in this entry. Developmental delay and seizures with or without movement abnormalities (DEDSM) [MIM:617836] An autosomal dominant neurodevelopmental disorder characterized by global developmental delay, variable intellectual disability, and early-onset seizures with a myoclonic component. Most patients have delayed motor development and show abnormal movements, including ataxia, dystonia, and tremor. The disease may be caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by phospholipids including cardiolipin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and phosphatidylserine.

Cofactor. Binds 1 magnesium ion per subunit.

Domain organisation. The catalytic site at NUS1-DHDDS interface accomodates both the allylic and the homoallylic IPP substrates to the S1 and S2 pockets respectively. The beta-phosphate groups of IPP substrates form hydrogen bonds with the RXG motif of NUS1 and four conserved residues of DHDDS (Arg-85, Arg-205, Arg-211 and Ser-213), while the allylic isopentenyl group is pointed toward the hydrophobic tunnel of the S1 pocket where the product elongation occurs.

Pathway. Protein modification; protein glycosylation. Lipid metabolism.

Miscellaneous. May be due to exon skipping.

Similarity. Belongs to the UPP synthase family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q86SQ9-1	1	yes
Q86SQ9-2	2
Q86SQ9-3	3
Q86SQ9-4	4

RefSeq proteins (5): NP_001230493, NP_001230494, NP_001306888, NP_079163, NP_995583* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001441	UPP_synth-like	Family
IPR018520	UPP_synth-like_CS	Conserved_site
IPR036424	UPP_synth-like_sf	Homologous_superfamily

Pfam: PF01255

Enzyme classification (BRENDA):

• EC 2.5.1.87 — ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific] (BRENDA: 12 organisms, 23 substrates, 2 inhibitors, 13 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ISOPENTENYL DIPHOSPHATE	0.0005–0.111	6
(2E,6E)-FARNESYL DIPHOSPHATE	0.0001–0.0149	3
DIMETHYLALLYL DIPHOSPHATE	0.0094	1
FARNESYL DIPHOSPHATE	0.001	1
GERANYL DIPHOSPHATE	0.0018	1
GERANYLGERANYL DIPHOSPHATE	0.0036	1

Catalyzed reactions (Rhea), 1 shown:

• n isopentenyl diphosphate + (2E,6E)-farnesyl diphosphate = a di-trans,poly-cis-polyprenyl diphosphate + n diphosphate (RHEA:53008)

UniProt features (63 total): helix 16, binding site 14, mutagenesis site 9, sequence variant 7, strand 7, turn 4, splice variant 3, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
7PAX	X-RAY DIFFRACTION	2
6Z1N	X-RAY DIFFRACTION	2.3
7PB0	X-RAY DIFFRACTION	2.3
6W2L	X-RAY DIFFRACTION	2.31
7PAY	X-RAY DIFFRACTION	2.4
9R08	X-RAY DIFFRACTION	2.4
7PB1	X-RAY DIFFRACTION	2.59
9R0E	X-RAY DIFFRACTION	2.82
9R0K	X-RAY DIFFRACTION	2.89

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86SQ9-F1	95.01	0.90

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (14): 34; 85; 85; 205; 211; 213; 34; 34; 35; 35; 37; 37 …

Mutagenesis-validated functional residues (9):

Position	Phenotype
12	markedly decreases phosphatidylinositol-mediated activation of cis-prenyltransferase activity resulting in products with
15	markedly decreases phosphatidylinositol-mediated activation of cis-prenyltransferase activity resulting in products with
19	markedly decreases phosphatidylinositol-mediated activation of cis-prenyltransferase activity resulting in products with
34	strongly reduced cis-prenyltransferase activity.
38	strongly reduced cis-prenyltransferase activity.
106–109	affects chain elongation resulting in shorter products.
306	delays cell growth; when associated with a-313 and a-317.
313	delays cell growth; when associated with a-306 and a-317.
317	delays cell growth; when associated with a-306 and a-313.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-446199	Synthesis of dolichyl-phosphate
R-HSA-4755609	Defective DHDDS causes RP59

MSigDB gene sets: 305 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_PROTEIN_N_LINKED_GLYCOSYLATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, TACAATC_MIR508, CACCAGC_MIR138, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, KEGG_TERPENOID_BACKBONE_BIOSYNTHESIS, HTF_01

GO Biological Process (6): dolichyl diphosphate biosynthetic process (GO:0006489), polyprenol biosynthetic process (GO:0016094), dolichyl monophosphate biosynthetic process (GO:0043048), obsolete protein glycosylation (GO:0006486), lipid metabolic process (GO:0006629), obsolete dolichol biosynthetic process (GO:0019408)

GO Molecular Function (6): ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific] activity (GO:0045547), metal ion binding (GO:0046872), prenyltransferase activity (GO:0004659), protein binding (GO:0005515), transferase activity (GO:0016740), transferase activity, transferring alkyl or aryl (other than methyl) groups (GO:0016765)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), dehydrodolichyl diphosphate synthase complex (GO:1904423), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Synthesis of substrates in N-glycan biosythesis	1
Diseases associated with glycosylation precursor biosynthesis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phospholipid biosynthetic process	2
dolichol-linked oligosaccharide biosynthetic process	1
isoprenoid biosynthetic process	1
polyprenol metabolic process	1
alcohol biosynthetic process	1
primary metabolic process	1
prenyl diphosphate synthase activity	1
cation binding	1
transferase activity, transferring alkyl or aryl (other than methyl) groups	1
binding	1
catalytic activity	1
transferase activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
polyprenyl diphosphate synthase complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2018 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DHDDS	NUS1	Q96E22	905
DHDDS	SRD5A3	Q9H8P0	735
DHDDS	DOLK	Q9UPQ8	716
DHDDS	FAM161A	Q3B820	695
DHDDS	DOLPP1	Q86YN1	691
DHDDS	DPM1	O60762	643
DHDDS	CERKL	Q49MI3	627
DHDDS	GUCA1B	Q9UMX6	614
DHDDS	ZNF513	Q8N8E2	599
DHDDS	IMPG2	Q9BZV3	583
DHDDS	CFAP418	Q96NL8	580
DHDDS	EYS	Q5T1H1	575
DHDDS	PCARE	A6NGG8	570
DHDDS	MPDU1	O75352	566
DHDDS	MVK	Q03426	559

IntAct

9 interactions, top by confidence:

A	B	Type	Score
DHDDS	NUS1	psi-mi:“MI:0407”(direct interaction)	0.730
DHDDS	NUS1	psi-mi:“MI:0915”(physical association)	0.730
NUS1	HSPA8	psi-mi:“MI:0914”(association)	0.530
TGFA	TNPO2	psi-mi:“MI:0914”(association)	0.350
HPCA	NMT2	psi-mi:“MI:0914”(association)	0.350
DHDDS	FOXP4	psi-mi:“MI:0914”(association)	0.350

BioGRID (22): NUS1 (Affinity Capture-MS), FOXP4 (Affinity Capture-MS), NPC2 (Two-hybrid), NUS1 (Affinity Capture-MS), FOXP4 (Affinity Capture-MS), DHDDS (Reconstituted Complex), DHDDS (Affinity Capture-MS), DHDDS (Positive Genetic), DHDDS (Affinity Capture-MS), ND1 (Two-hybrid), DHDDS (Affinity Capture-MS), NUS1 (Affinity Capture-MS), DHDDS (Affinity Capture-MS), FOXP4 (Affinity Capture-MS), DHDDS (Negative Genetic)

ESM2 similar proteins: A2VD33, A5PK19, A6QPU5, O75792, O95352, P11172, P13439, P31754, P41111, Q02053, Q0ZHH6, Q14181, Q16798, Q2TBT5, Q32PX9, Q3MHH4, Q3TX08, Q3V384, Q5EBA1, Q5R514, Q5R7A2, Q5RF36, Q5U209, Q641W2, Q641Y5, Q6DD88, Q6IQS6, Q80YD1, Q86SQ9, Q8BIP0, Q8BMF3, Q8BML9, Q8N6R0, Q8WV93, Q91YH5, Q91YR5, Q921Q3, Q96T60, Q9BT22, Q9CWY8

Diamond homologs: A0R0S4, K4D3U9, K7WCI9, K7X479, O14171, O26334, O29049, O31751, O59258, O80458, O82827, O84456, O87197, P0DH32, P0DH33, P35196, P38118, P38119, P58563, P60478, P60482, P9WFF6, P9WFF7, Q03175, Q1RII8, Q47RM6, Q4ULR6, Q55482, Q58767, Q5F5X2, Q5H1E5, Q5JGE1, Q5L0J8, Q5M1N6, Q5M677, Q5SH15, Q5X9U4, Q6HEZ2, Q6KZ89, Q720A7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	24
Uncertain significance	280
Likely benign	260
Benign	15

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1076541	NM_205861.3(DHDDS):c.374_377dup (p.Pro128fs)	Pathogenic
1214981	NM_205861.3(DHDDS):c.109C>T (p.Arg37Cys)	Pathogenic
1400385	NM_205861.3(DHDDS):c.714G>A (p.Trp238Ter)	Pathogenic
1415429	NM_205861.3(DHDDS):c.510dup (p.Trp171fs)	Pathogenic
1525125	NC_000001.10:g.(?26764639)(26764795_?)del	Pathogenic
2021747	NM_205861.3(DHDDS):c.100del (p.Asp34fs)	Pathogenic
2426900	NC_000001.10:g.(?26784272)(26795632_?)del	Pathogenic
2426903	NC_000001.10:g.(?26757796)(26764723_?)del	Pathogenic
2664983	NM_205861.3(DHDDS):c.698C>G (p.Pro233Arg)	Pathogenic
30709	NM_205861.3(DHDDS):c.124A>G (p.Lys42Glu)	Pathogenic
3247807	NC_000001.10:g.(?26759437)(26774171_?)del	Pathogenic
3725536	NM_205861.3(DHDDS):c.35G>A (p.Trp12Ter)	Pathogenic
4803762	NM_205861.3(DHDDS):c.517del (p.Val173fs)	Pathogenic
488193	NM_205861.3(DHDDS):c.632G>A (p.Arg211Gln)	Pathogenic
488194	NM_205861.3(DHDDS):c.192G>A (p.Trp64Ter)	Pathogenic
546177	NM_205861.3(DHDDS):c.109C>A (p.Arg37Ser)	Pathogenic
570739	NM_205861.3(DHDDS):c.614G>A (p.Arg205Gln)	Pathogenic
1066115	NM_205861.3(DHDDS):c.658-2A>G	Likely pathogenic
1187979	NM_205861.3(DHDDS):c.161_162delinsAA (p.Gly54Glu)	Likely pathogenic
1297155	NM_205861.3(DHDDS):c.616A>G (p.Thr206Ala)	Likely pathogenic
1520232	NM_205861.3(DHDDS):c.441-2A>T	Likely pathogenic
1525136	NC_000001.10:g.(?26784272)(26784406_?)del	Likely pathogenic
1722460	NM_205861.3(DHDDS):c.644del (p.Phe215fs)	Likely pathogenic
1971743	NM_205861.3(DHDDS):c.650_657+54del	Likely pathogenic
2577589	NM_205861.3(DHDDS):c.925C>T (p.Arg309Ter)	Likely pathogenic
2637052	NM_205861.3(DHDDS):c.638G>A (p.Ser213Asn)	Likely pathogenic
2674799	NM_205861.3(DHDDS):c.705T>A (p.Tyr235Ter)	Likely pathogenic
2674800	NM_205861.3(DHDDS):c.568A>T (p.Lys190Ter)	Likely pathogenic
2674802	NM_205861.3(DHDDS):c.665_668del (p.His222fs)	Likely pathogenic
2836308	NM_205861.3(DHDDS):c.657+1G>A	Likely pathogenic

SpliceAI

1310 predictions. Top by Δscore:

Variant	Effect	Δscore
1:26433006:AAG:A	donor_loss	1.0000
1:26433007:AG:A	donor_loss	1.0000
1:26433008:GG:G	donor_loss	1.0000
1:26438165:C:G	acceptor_gain	1.0000
1:26438166:A:AG	acceptor_gain	1.0000
1:26438167:G:GG	acceptor_gain	1.0000
1:26438167:GGC:G	acceptor_gain	1.0000
1:26438167:GGCA:G	acceptor_gain	1.0000
1:26438249:G:GT	donor_gain	1.0000
1:26438281:TGAG:T	donor_loss	1.0000
1:26438286:T:G	donor_loss	1.0000
1:26442866:G:GT	donor_gain	1.0000
1:26442869:GAAAA:G	donor_gain	1.0000
1:26442872:AA:A	donor_gain	1.0000
1:26442872:AAG:A	donor_loss	1.0000
1:26442873:AG:A	donor_loss	1.0000
1:26442874:G:C	donor_loss	1.0000
1:26442874:G:GG	donor_gain	1.0000
1:26442875:T:TC	donor_loss	1.0000
1:26446309:T:TA	acceptor_gain	1.0000
1:26446312:TCAGG:T	acceptor_loss	1.0000
1:26446313:CAG:C	acceptor_loss	1.0000
1:26446314:A:AG	acceptor_gain	1.0000
1:26446315:G:GG	acceptor_gain	1.0000
1:26446315:GGGA:G	acceptor_gain	1.0000
1:26446428:AACAA:A	donor_gain	1.0000
1:26446429:ACAA:A	donor_gain	1.0000
1:26446430:CAA:C	donor_gain	1.0000
1:26446430:CAAG:C	donor_loss	1.0000
1:26446431:AA:A	donor_gain	1.0000

AlphaMissense

2175 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:26438199:T:A	I32K	1.000
1:26438204:G:C	D34H	1.000
1:26438205:A:C	D34A	1.000
1:26438205:A:G	D34G	1.000
1:26438205:A:T	D34V	1.000
1:26438206:C:A	D34E	1.000
1:26438206:C:G	D34E	1.000
1:26438207:G:A	G35R	1.000
1:26438207:G:C	G35R	1.000
1:26438207:G:T	G35W	1.000
1:26438208:G:A	G35E	1.000
1:26438208:G:T	G35V	1.000
1:26442796:C:A	N82K	1.000
1:26442796:C:G	N82K	1.000
1:26460073:T:A	W232R	1.000
1:26460073:T:C	W232R	1.000
1:26438193:C:A	A30E	0.999
1:26438199:T:G	I32R	0.999
1:26438203:G:A	M33I	0.999
1:26438203:G:C	M33I	0.999
1:26438203:G:T	M33I	0.999
1:26438204:G:A	D34N	0.999
1:26438204:G:T	D34Y	0.999
1:26438208:G:C	G35A	0.999
1:26438212:C:A	N36K	0.999
1:26438212:C:G	N36K	0.999
1:26438214:G:C	R37P	0.999
1:26438216:C:A	R38S	0.999
1:26438217:G:C	R38P	0.999
1:26438223:C:A	A40D	0.999

dbSNP variants (sampled 300 via entrez): RS1000031199 (1:26470506 T>C,G), RS1000035502 (1:26467177 C>A,G), RS1000043711 (1:26462034 T>C), RS1000090452 (1:26466826 A>G), RS1000126228 (1:26450363 T>A,C), RS1000285932 (1:26460794 G>A), RS1000318909 (1:26470738 G>A), RS1000377162 (1:26435888 C>T), RS1000401361 (1:26457315 A>C), RS1000497526 (1:26431859 AT>A), RS1000605923 (1:26436926 T>C), RS1000620811 (1:26443582 G>T), RS1000682304 (1:26434751 C>G,T), RS1000746478 (1:26457056 CAG>C), RS1000746644 (1:26436126 G>A,T)

Disease associations

OMIM: gene MIM:608172 | disease phenotypes: MIM:613861, MIM:617836, MIM:268000

GenCC curated gene-disease

Disease	Classification	Inheritance
retinitis pigmentosa 59	Definitive	Autosomal recessive
developmental delay and seizures with or without movement abnormalities	Strong	Autosomal dominant
undetermined early-onset epileptic encephalopathy	Supportive	Autosomal dominant
retinitis pigmentosa	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
DHDDS-CDG	Definitive	AR

Mondo (7): retinitis pigmentosa 59 (MONDO:0013468), developmental delay and seizures with or without movement abnormalities (MONDO:0044326), retinitis pigmentosa (MONDO:0019200), inherited retinal dystrophy (MONDO:0019118), DHDDS-CDG (MONDO:1040054), congenital disorder of glycosylation, type Ibb (MONDO:0800353), undetermined early-onset epileptic encephalopathy (MONDO:0018614)

Orphanet (2): Retinitis pigmentosa (Orphanet:791), OBSOLETE: Inherited retinal disorder (Orphanet:71862)

HPO phenotypes

97 total (30 of 97 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000083	Renal insufficiency
HP:0000252	Microcephaly
HP:0000348	High forehead
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000494	Downslanted palpebral fissures
HP:0000501	Glaucoma
HP:0000504	Abnormality of vision
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000543	Optic disc pallor
HP:0000546	Retinal degeneration
HP:0000551	Color vision defect
HP:0000563	Keratoconus
HP:0000602	Ophthalmoplegia
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000662	Nyctalopia
HP:0000668	Hypodontia
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000750	Delayed speech and language development

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST007429_54	Lung function (FVC)	8.000000e-10
GCST007429_55	Lung function (FVC)	8.000000e-09
GCST007430_13	Peak expiratory flow	4.000000e-07
GCST007432_28	FEV1	3.000000e-11
GCST007432_29	FEV1	2.000000e-12
GCST011124_13	Caffeine consumption from tea	2.000000e-08
GCST011353_33	Serum alkaline phosphatase levels	4.000000e-10

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004312	vital capacity
EFO:0009718	peak expiratory flow
EFO:0004314	forced expiratory volume
EFO:0010091	tea consumption measurement
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression	3
Arsenic	affects methylation, increases abundance, increases expression	2
Cyclosporine	increases expression	2
dicrotophos	increases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	decreases expression	1
GW 4064	affects cotreatment, decreases expression, increases expression	1
GW 7647	affects cotreatment, increases expression	1
picoxystrobin	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Doxorubicin	decreases expression	1
Ozone	affects expression, increases abundance	1
Phthalic Acids	increases methylation	1
Valproic Acid	increases methylation	1
Oleic Acid	affects cotreatment, decreases expression, increases expression	1

Clinical trials (associated diseases)

259 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT00063765	PHASE1	COMPLETED	Evaluation of Safety of Ciliary Neurotrophic Factor Implants in the Eye
NCT00065455	PHASE1	COMPLETED	Investigating the Effect of Vitamin A Supplementation on Retinitis Pigmentosa
NCT00458575	PHASE1	TERMINATED	A Study to Evaluate the Safety of CNTO 2476 in Patients With Advanced Retinitis Pigmentosa