GRAMD2A

Summary

GRAMD2A (GRAM domain containing 2A, HGNC:27287) is a protein-coding gene on chromosome 15q23, encoding GRAM domain-containing protein 2A (Q8IUY3). Participates in the organization of endoplasmic reticulum-plasma membrane contact sites (EPCS) with pleiotropic functions including STIM1 recruitment and calcium homeostasis.

Enables phosphatidylinositol-4,5-bisphosphate binding activity. Involved in endoplasmic reticulum-plasma membrane tethering and regulation of store-operated calcium entry. Located in endoplasmic reticulum membrane; organelle membrane contact site; and plasma membrane.

Source: NCBI Gene 196996 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 57 total
• MANE Select transcript: NM_001012642

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27287
Approved symbol	GRAMD2A
Name	GRAM domain containing 2A
Location	15q23
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000175318
Ensembl biotype	protein_coding
OMIM	620181
Entrez	196996

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 7 protein_coding, 5 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000309731, ENST00000562288, ENST00000563133, ENST00000564129, ENST00000564184, ENST00000564773, ENST00000565233, ENST00000567029, ENST00000567637, ENST00000567662, ENST00000568594, ENST00000569450, ENST00000570275, ENST00000864980, ENST00000940893, ENST00000940894

RefSeq mRNA: 1 — MANE Select: NM_001012642 NM_001012642

CCDS: CCDS32283

Canonical transcript exons

ENST00000309731 — 12 exons

Exon	Start	End
ENSE00001222531	72166632	72166703
ENSE00001418794	72197731	72197787
ENSE00001433735	72159806	72162012
ENSE00003462799	72169847	72169939
ENSE00003507808	72167736	72167839
ENSE00003507853	72162273	72162377
ENSE00003523106	72168939	72168996
ENSE00003526076	72168491	72168566
ENSE00003655366	72163266	72163476
ENSE00003680586	72163613	72163757
ENSE00003690683	72165354	72165410
ENSE00003787842	72166994	72167092

Expression profiles

Bgee: expression breadth ubiquitous, 174 present calls, max score 97.23.

FANTOM5 (CAGE): breadth broad, TPM avg 0.8897 / max 158.7005, expressed in 210 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
150781	0.3719	143
150776	0.1118	19
150774	0.0847	22
150777	0.0537	18
150782	0.0477	22
150770	0.0371	16
150779	0.0350	12
150780	0.0343	16
150771	0.0232	13
150772	0.0214	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oviduct epithelium	UBERON:0004804	97.23	gold quality
tibia	UBERON:0000979	96.52	gold quality
placenta	UBERON:0001987	92.25	gold quality
right uterine tube	UBERON:0001302	89.90	gold quality
right lobe of thyroid gland	UBERON:0001119	89.54	gold quality
left lobe of thyroid gland	UBERON:0001120	89.45	gold quality
thyroid gland	UBERON:0002046	88.41	gold quality
right lung	UBERON:0002167	86.79	gold quality
metanephros cortex	UBERON:0010533	86.78	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	86.26	gold quality
cauda epididymis	UBERON:0004360	85.91	gold quality
corpus epididymis	UBERON:0004359	84.74	gold quality
upper lobe of left lung	UBERON:0008952	84.57	gold quality
upper lobe of lung	UBERON:0008948	83.59	gold quality
fallopian tube	UBERON:0003889	83.53	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.50	gold quality
mucosa of transverse colon	UBERON:0004991	80.46	gold quality
lung	UBERON:0002048	79.81	gold quality
ileal mucosa	UBERON:0000331	79.54	silver quality
caput epididymis	UBERON:0004358	79.35	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.48	gold quality
left uterine tube	UBERON:0001303	78.37	gold quality
bronchial epithelial cell	CL:0002328	78.08	gold quality
bronchus	UBERON:0002185	76.86	gold quality
caudate nucleus	UBERON:0001873	76.14	gold quality
transverse colon	UBERON:0001157	75.23	gold quality
small intestine Peyer’s patch	UBERON:0003454	74.49	gold quality
amniotic fluid	UBERON:0000173	74.39	silver quality
tibial nerve	UBERON:0001323	74.06	gold quality
minor salivary gland	UBERON:0001830	73.52	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.18
E-MTAB-5061	no	3.70

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

77 targeting GRAMD2A, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-4516	99.61	67.78	3390

Literature-anchored findings (GeneRIF, showing 1)

• GRAMD2a, but not GRAMD1a, co-localizes with the E-Syt2/3 tethers at endoplasmic reticulum-plasma membrane contact sites in a phosphatidylinositol phosphate lipid-dependent manner. Data from an analysis of cells lacking GRAMD2a suggest that it is an organizer of the membrane contact sites with pleiotropic functions including calcium homeostasis. (PMID:29469807)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gramd2aa	ENSDARG00000103736
mus_musculus	Gramd2a	ENSMUSG00000074259
rattus_norvegicus	Gramd2a	ENSRNOG00000025979
drosophila_melanogaster	GramD1B	FBGN0085423
caenorhabditis_elegans	ZC328.3	WBGENE00022593

Paralogs (4): GRAMD1B (ENSG00000023171), GRAMD1A (ENSG00000089351), GRAMD2B (ENSG00000155324), GRAMD1C (ENSG00000178075)

Protein

Protein identifiers

GRAM domain-containing protein 2A — Q8IUY3 (reviewed: Q8IUY3)

All UniProt accessions (5): Q8IUY3, H3BTA1, H3BTF7, H3BTY3, H3BUI8

UniProt curated annotations — full annotation on UniProt →

Function. Participates in the organization of endoplasmic reticulum-plasma membrane contact sites (EPCS) with pleiotropic functions including STIM1 recruitment and calcium homeostasis. Constitutive tether that co-localize with ESYT2/3 tethers at endoplasmic reticulum-plasma membrane contact sites in a phosphatidylinositol lipid-dependent manner. Pre-marks the subset of phosphtidylinositol 4,5-biphosphate (PI(4,5)P2)-enriched EPCS destined for the store operated calcium entry pathway (SOCE).

Subcellular location. Endoplasmic reticulum membrane. Cell membrane.

Domain organisation. GRAM domain is required for specific location to endoplasmic reticulum-plasma membrane contact sites (EPCS). Mediates interaction to phosphatidylinositol lipids and binding to plasma membrane.

RefSeq proteins (1): NP_001012660* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004182	GRAM	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR042624	RAMD2A	Family

Pfam: PF02893

UniProt features (6 total): compositionally biased region 2, chain 1, transmembrane region 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IUY3-F1	63.67	0.29

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 61 (showing top): GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_MEMBRANE_DOCKING, CHARAFE_BREAST_CANCER_BASAL_VS_MESENCHYMAL_UP, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOZGIT_ESR1_TARGETS_UP, GOBP_ENDOPLASMIC_RETICULUM_ORGANIZATION, chr15q23, GOBP_REGULATION_OF_TRANSPORT, GOBP_REGULATION_OF_MONOATOMIC_ION_TRANSPORT, GOBP_ORGANELLE_LOCALIZATION, GOCC_ORGANELLE_MEMBRANE_CONTACT_SITE, GOCC_NUCLEAR_OUTER_MEMBRANE_ENDOPLASMIC_RETICULUM_MEMBRANE_NETWORK, GOCC_ORGANELLE_SUBCOMPARTMENT, GOMF_PHOSPHATIDYLINOSITOL_4_5_BISPHOSPHATE_BINDING, GOMF_PHOSPHATIDYLINOSITOL_PHOSPHATE_BINDING

GO Biological Process (2): obsolete endoplasmic reticulum-plasma membrane tethering (GO:0061817), regulation of store-operated calcium entry (GO:2001256)

GO Molecular Function (4): phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), phosphatidylinositol binding (GO:0035091), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (6): endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), organelle membrane contact site (GO:0044232), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
binding	2
store-operated calcium entry	1
regulation of calcium ion transport	1
phosphatidylinositol phosphate binding	1
phosphatidylinositol bisphosphate binding	1
anion binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
organelle	1
intracellular anatomical structure	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

478 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GRAMD2A	ESYT3	A0FGR9	623
GRAMD2A	ESYT1	Q9BSJ8	575
GRAMD2A	ESYT2	A0FGR8	487
GRAMD2A	ERICH2	A1L162	474
GRAMD2A	DCST1	Q5T197	469
GRAMD2A	OSBPL5	Q9H0X9	436
GRAMD2A	UBL7	Q96S82	419
GRAMD2A	STIM1	Q13586	418
GRAMD2A	ALDH8A1	Q9H2A2	415
GRAMD2A	OSBPL8	Q9BZF1	403
GRAMD2A	C2CD2L	O14523	400
GRAMD2A	PITPNM1	O00562	396
GRAMD2A	ANO8	Q9HCE9	395
GRAMD2A	TECRL	Q5HYJ1	379
GRAMD2A	VMO1	Q7Z5L0	376

IntAct

13 interactions, top by confidence:

A	B	Type	Score
BNIP2	GRAMD2A	psi-mi:“MI:0915”(physical association)	0.560
EMD	GRAMD2A	psi-mi:“MI:0915”(physical association)	0.560
GRAMD2A	TRAF3IP3	psi-mi:“MI:0915”(physical association)	0.560
GRAMD2B	EFCAB14	psi-mi:“MI:0914”(association)	0.530
GRAMD2A	ACTN3	psi-mi:“MI:0914”(association)	0.350
GRAMD1B	TRAPPC10	psi-mi:“MI:0914”(association)	0.350
BNIP2	GRAMD2A	psi-mi:“MI:0915”(physical association)	0.000
TRAF3IP3	GRAMD2A	psi-mi:“MI:0915”(physical association)	0.000
EMD	GRAMD2A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (10): GRAMD2 (Affinity Capture-MS), GRAMD2 (Two-hybrid), GRAMD2 (Two-hybrid), GRAMD2 (Two-hybrid), TUBA3C (Affinity Capture-MS), TUBA8 (Affinity Capture-MS), ACTN3 (Affinity Capture-MS), GRAMD2 (Affinity Capture-MS), GRAMD2 (Affinity Capture-MS), GRAMD2 (Affinity Capture-RNA)

ESM2 similar proteins: A0A8M9QN10, A2AQ14, A2ARM1, A2CI97, A2CI98, A2CJ06, A5D7N9, B1MT51, B2RZC4, B5SNH4, O43147, O43482, O70173, P0C6P5, P59729, P70371, P97433, Q3UHA3, Q5BIW4, Q5BK24, Q5EB20, Q5I0F1, Q5PQS0, Q5SSH7, Q5U3H9, Q68UT5, Q6GR31, Q6IRN0, Q6NV72, Q6P4K6, Q6ZUJ8, Q7TSI1, Q7Z2Z1, Q7Z4M0, Q80VA5, Q8BPZ8, Q8BQ33, Q8IUY3, Q8ND61, Q8WYP3

Diamond homologs: A3KGB4, F4HVW5, O42976, O95759, P38800, P43560, Q06681, Q3KR37, Q3KR56, Q3UYK3, Q3V3G7, Q5FVG8, Q5R8N8, Q5RC33, Q6PEM6, Q6ZT07, Q80TI0, Q8IUY3, Q8IYS0, Q8MVR1, Q8VEF1, Q96CP6, Q96HH9, Q9Z1A9, Q9ZVT9, Q54HC6, Q54IL5, Q5B4C9, Q8CI52, Q8W4D4, Q08001, Q5SVR0, Q66K14, A1CFB3, A2QNQ5, A7KAN4, B0R0W9, C4B4E5, Q0CKU4, Q0IIM8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	47
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2752 predictions. Top by Δscore:

Variant	Effect	Δscore
15:72163264:A:AC	donor_gain	1.0000
15:72163265:C:CC	donor_gain	1.0000
15:72163265:CAG:C	donor_gain	1.0000
15:72163265:CAGCA:C	donor_gain	1.0000
15:72166700:TATA:T	acceptor_gain	1.0000
15:72166702:TA:T	acceptor_gain	1.0000
15:72166704:C:CC	acceptor_gain	1.0000
15:72166710:CA:C	acceptor_gain	1.0000
15:72166711:A:AC	acceptor_gain	1.0000
15:72166711:A:C	acceptor_gain	1.0000
15:72166989:CTGA:C	donor_loss	1.0000
15:72166991:GACC:G	donor_loss	1.0000
15:72166993:CCTT:C	donor_gain	1.0000
15:72167089:CCAC:C	acceptor_gain	1.0000
15:72167090:CACC:C	acceptor_gain	1.0000
15:72167092:CCT:C	acceptor_loss	1.0000
15:72168997:C:CC	acceptor_gain	1.0000
15:72169841:CCTCA:C	donor_loss	1.0000
15:72169842:CTCA:C	donor_loss	1.0000
15:72169843:TCAC:T	donor_loss	1.0000
15:72169844:CACC:C	donor_loss	1.0000
15:72169845:A:AC	donor_gain	1.0000
15:72169845:ACC:A	donor_loss	1.0000
15:72169846:C:CA	donor_loss	1.0000
15:72169846:C:CC	donor_gain	1.0000
15:72169937:TTG:T	acceptor_gain	1.0000
15:72169938:TG:T	acceptor_gain	1.0000
15:72169939:GCT:G	acceptor_loss	1.0000
15:72169940:C:CC	acceptor_gain	1.0000
15:72162376:TC:T	acceptor_gain	0.9900

AlphaMissense

2321 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:72167766:G:C	F114L	0.998
15:72167766:G:T	F114L	0.998
15:72167768:A:G	F114L	0.998
15:72166696:A:G	F160S	0.997
15:72167767:A:G	F114S	0.997
15:72167769:G:C	C113W	0.997
15:72167016:A:T	I150N	0.996
15:72168539:A:C	Y74D	0.996
15:72167025:C:T	G147E	0.995
15:72167771:A:G	C113R	0.995
15:72167792:A:C	Y106D	0.995
15:72167794:A:G	L105P	0.995
15:72168525:A:C	F78L	0.995
15:72168525:A:T	F78L	0.995
15:72168526:A:G	F78S	0.995
15:72168527:A:G	F78L	0.995
15:72166695:A:C	F160L	0.994
15:72166695:A:T	F160L	0.994
15:72166697:A:G	F160L	0.994
15:72168538:T:G	Y74S	0.994
15:72166696:A:C	F160C	0.993
15:72167786:A:G	S108P	0.993
15:72167801:C:G	G103R	0.993
15:72167016:A:C	I150S	0.992
15:72167022:A:G	L148P	0.992
15:72167767:A:C	F114C	0.992
15:72167788:A:T	I107N	0.992
15:72167797:C:G	R104P	0.992
15:72167824:A:G	L95P	0.992
15:72167054:T:A	K137N	0.991

dbSNP variants (sampled 300 via entrez): RS1000080554 (15:72163927 T>A,C), RS1000252095 (15:72184503 C>G), RS1000330873 (15:72187829 CT>C,CTT), RS1000380375 (15:72178790 G>A), RS1000383267 (15:72188245 G>A), RS1000456044 (15:72197244 G>A), RS1000512320 (15:72195436 C>CG), RS1000607566 (15:72160865 C>A,T), RS1000674514 (15:72189373 A>T), RS1000725029 (15:72189912 C>T), RS1000758468 (15:72197466 A>G), RS1000823778 (15:72174439 G>A,C), RS1000891342 (15:72183061 C>G,T), RS1000974436 (15:72195672 C>T), RS1001012681 (15:72160538 T>C)

Disease associations

OMIM: gene MIM:620181 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001823_21	Metabolite levels (HVA/MHPG ratio)	2.000000e-06
GCST008156_69	Hip circumference adjusted for BMI	5.000000e-06
GCST010083_231	Hemoglobin levels	9.000000e-10
GCST010083_289	Hemoglobin levels	1.000000e-14

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005131	HVA measurement
EFO:0005133	MHPG measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004509	hemoglobin measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Smoke	decreases expression	2
aristolochic acid I	increases expression	1
bisphenol A	increases methylation, decreases expression	1
lead acetate	decreases expression	1
sodium arsenite	decreases expression	1
tobacco tar	decreases expression	1
cupric chloride	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
entinostat	increases expression	1
clothianidin	decreases expression	1
Air Pollutants	increases abundance, decreases expression	1
Benzo(a)pyrene	increases methylation	1
Diethylhexyl Phthalate	increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases expression	1
Lithium Chloride	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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