HHLA2

Summary

HHLA2 (HHLA2 member of B7 family, HGNC:4905) is a protein-coding gene on chromosome 3q13.13, encoding HERV-H LTR-associating protein 2 (Q9UM44). Through interaction with TMIGD2, costimulates T-cells in the context of TCR-mediated activation.

This gene encodes a protein ligand found on the surface of monocytes. The encoded protein is thought to regulate cell-mediated immunity by binding to a receptor on T lymphocytes and inhibiting the proliferation of these cells. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 11148 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 65 total
• MANE Select transcript: NM_001282556

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4905
Approved symbol	HHLA2
Name	HHLA2 member of B7 family
Location	3q13.13
Locus type	gene with protein product
Status	Approved
Aliases	B7H7, B7-H5, B7y, B7-H7
Ensembl gene	ENSG00000114455
Ensembl biotype	protein_coding
OMIM	604371
Entrez	11148

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 35 protein_coding

ENST00000357759, ENST00000462629, ENST00000463019, ENST00000467282, ENST00000467562, ENST00000467761, ENST00000482099, ENST00000489514, ENST00000491820, ENST00000896068, ENST00000896069, ENST00000896070, ENST00000896071, ENST00000896072, ENST00000896073, ENST00000896074, ENST00000896075, ENST00000896076, ENST00000896077, ENST00000896078, ENST00000896079, ENST00000896080, ENST00000896081, ENST00000896082, ENST00000896083, ENST00000896084, ENST00000896085, ENST00000896086, ENST00000896087, ENST00000896088, ENST00000896089, ENST00000896090, ENST00000941561, ENST00000941562, ENST00000941563

RefSeq mRNA: 6 — MANE Select: NM_001282556 NM_001282556, NM_001282557, NM_001282558, NM_001282559, NM_001370244, NM_007072

CCDS: CCDS46883, CCDS63713, CCDS74975

Canonical transcript exons

ENST00000467761 — 10 exons

Exon	Start	End
ENSE00000774924	108362342	108362446
ENSE00001075442	108355115	108355381
ENSE00001075443	108357844	108358161
ENSE00001226036	108375750	108375800
ENSE00001226087	108376493	108376557
ENSE00001731621	108377258	108378285
ENSE00001865028	108310655	108310741
ENSE00001899076	108296548	108296599
ENSE00003488344	108351788	108351877
ENSE00003489169	108353427	108353780

Expression profiles

Bgee: expression breadth ubiquitous, 112 present calls, max score 97.33.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.9782 / max 403.8366, expressed in 65 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
37819	0.6948	53
37817	0.0825	16
37815	0.0775	12
37818	0.0765	19
37816	0.0469	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
rectum	UBERON:0001052	97.33	gold quality
mucosa of transverse colon	UBERON:0004991	95.80	gold quality
jejunal mucosa	UBERON:0000399	93.97	gold quality
colonic mucosa	UBERON:0000317	92.60	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.09	gold quality
secondary oocyte	CL:0000655	90.99	gold quality
oocyte	CL:0000023	90.36	gold quality
gall bladder	UBERON:0002110	89.33	gold quality
duodenum	UBERON:0002114	88.67	gold quality
ileal mucosa	UBERON:0000331	85.80	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.50	gold quality
transverse colon	UBERON:0001157	84.38	gold quality
small intestine Peyer’s patch	UBERON:0003454	83.07	gold quality
small intestine	UBERON:0002108	82.30	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.11	gold quality
islet of Langerhans	UBERON:0000006	80.50	gold quality
bronchial epithelial cell	CL:0002328	79.96	gold quality
epithelium of bronchus	UBERON:0002031	77.10	gold quality
bronchus	UBERON:0002185	75.98	gold quality
intestine	UBERON:0000160	75.50	gold quality
right uterine tube	UBERON:0001302	73.88	gold quality
large intestine	UBERON:0000059	72.95	gold quality
colon	UBERON:0001155	72.11	gold quality
vermiform appendix	UBERON:0001154	72.04	gold quality
colonic epithelium	UBERON:0000397	71.05	gold quality
jejunum	UBERON:0002115	70.05	gold quality
caecum	UBERON:0001153	67.41	gold quality
pancreas	UBERON:0001264	66.96	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	65.37	gold quality
adult mammalian kidney	UBERON:0000082	65.26	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	24.38
E-MTAB-5061	yes	17.85
E-ANND-3	yes	8.89

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

71 targeting HHLA2, 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-4673	100.00	66.64	1490
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6875-3P	99.82	70.26	2983
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-92A-2-5P	99.75	67.01	2164
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107

Literature-anchored findings (GeneRIF, showing 40)

• Data indicate that HHLA2 protein was predominantly found on cell membranes with some in the cytoplasm. (PMID:23716685)
• B7 homologue 5 (B7-H5), was identified as a specific ligand for CD28H (PMID:23784006)
• Low B7-H5 expression is associated with pancreatic adenocarcinomas. (PMID:25519928)
• The HHLA2 pathway represents a novel immunosuppressive mechanism within the tumor microenvironment. (PMID:25549724)
• HHLA2 protein expression was evaluated in primary tumor specimens and metastatic disease using an osteosarcoma tumor microarray. HHLA2 was expressed in almost all metastatic disease specimens and was more prevalent than in primary specimens without known metastases. (PMID:27531281)
• HHLA2 was not detected in most of normal lung tissue but expressed in 66% of NSCLC across different subtypes. In particular, EGFR-mutated NSCLC was significantly associated with higher tumor HHLA2 expression in both discovery and validation lung cancer cohorts. HHLA2 is widely expressed in NSCLC and is associated with EGFR mutation and high TILs in lung adenocarcinoma. (PMID:27553831)
• Up-regulation of HHLA2, a novel immune checkpoint protein, in pancreatic ductal adenocarcinoma predicts post-surgical survival. (PMID:30447255)
• B7-H5/CD28H is a co-stimulatory signal pathway, and expression of B7-H5 is associated with improved disease prognosis in patients with pancreatic cancer. (PMID:30548441)
• Kaplan-Meier survival curve revealed that high HHLA2 expression was significantly correlated with the poor RFS and OS of BUC patients (both p < 0.05), and the ROC curve showed HHLA2 could be a good diagnostic marker (PMID:30602154)
• Results found HHLA2 more commonly expressed and possesses significant prognostic value compared with PD-L1 in intrahepatic cholangiocarcinoma (ICC) cases. High HHLA2 is frequent in PD-L1 negative cases and is associated with fewer infiltrating cytotoxic and regulatory T cells. (PMID:30885276)
• High HHLA2 expression levels in oral squamous cell carcinoma cells indicate poor prognosis. HHLA2 expression levels were positively correlated with TIM3, LAG3, B7H4, VISTA and B7H3 levels. (PMID:31089395)
• Low HHLA2 expression is associated with malignant glioma. (PMID:31578594)
• HHLA2 and PD-L1 co-expression predicts poor prognosis in patients with clear cell renal cell carcinoma. (PMID:31959726)
• B7-H7 (HHLA2) inhibits T-cell activation and proliferation in the presence of TCR and CD28 signaling. (PMID:32005952)
• B7-H4 and HHLA2, members of B7 family, are aberrantly expressed in EGFR mutated lung adenocarcinoma. (PMID:32853956)
• KIR3DL3 Is an Inhibitory Receptor for HHLA2 that Mediates an Alternative Immunoinhibitory Pathway to PD1. (PMID:33229411)
• H Long Terminal Repeat-Associating 2 (HHLA2) is a Biomarker of Advanced Stage Hepatocellular Carcinoma and Promotes Tumor Cell Development In Vitro. (PMID:33990536)
• B7-H7 Is Inducible on T Cells to Regulate Their Immune Response and Serves as a Marker for Exhaustion. (PMID:34140952)
• HHLA2 deficiency inhibits non-small cell lung cancer progression and THP-1 macrophage M2 polarization. (PMID:34152094)
• KIR3DL3-HHLA2 is a human immunosuppressive pathway and a therapeutic target. (PMID:34244312)
• Prognostic value of HHLA2 expression in solid tumors: A meta-analysis based on the Chinese population. (PMID:34397730)
• Interferon Gamma-Induced Interferon Regulatory Factor 1 Activates Transcription of HHLA2 and Induces Immune Escape of Hepatocellular Carcinoma Cells. (PMID:34536158)
• Association analysis of B7-H3 and B7-H4 gene single nucleotide polymorphisms in susceptibility to ankylosing spondylitis in eastern Chinese Han population. (PMID:34555253)
• HHLA2 Immune Checkpoint Is a Novel Prognostic Predictor in Hepatocellular Carcinoma. (PMID:35084443)
• Coexpression of HHLA2 and PD-L1 on Tumor Cells Independently Predicts the Survival of Spinal Chordoma Patients. (PMID:35145510)
• HHLA2 Activates the JAK/STAT Signaling Pathway by Binding to TMIGD2 in Hepatocellular Carcinoma Cells. (PMID:35175496)
• Different clinical significance of novel B7 family checkpoints VISTA and HHLA2 in human lung adenocarcinoma. (PMID:35187955)
• High expression of HHLA2 predicts poor prognosis in medullary thyroid carcinoma. (PMID:35348687)
• Comprehensive Analysis of HHLA2 as a Prognostic Biomarker and Its Association With Immune Infiltrates in Hepatocellular Carcinoma. (PMID:35371079)
• Human endogenous retrovirus-H long terminal repeat-associating 2: The next immune checkpoint for antitumour therapy. (PMID:35439678)
• Decrease of Membrane B7-H5 on CD14+ Cells in Severe Acute Pancreatitis Is Related to RANSON Scores and APACHE II Scores. (PMID:35761035)
• The methyltransferase METTL3 promotes tumorigenesis via mediating HHLA2 mRNA m6A modification in human renal cell carcinoma. (PMID:35794583)
• HHLA2 promotes tumor progression by long noncoding RNA H19 in human gallbladder cancer. (PMID:35920182)
• KIR3DL3-HHLA2 and TMIGD2-HHLA2 pathways: The dual role of HHLA2 in immune responses and its potential therapeutic approach for cancer immunotherapy. (PMID:35933091)
• HHLA2 predicts improved prognosis of anti-PD-1/PD-L1 immunotherapy in patients with melanoma. (PMID:36003385)
• Silencing tumor-intrinsic HHLA2 potentiates the anti-tumoral effect of paclitaxel on MG63 cells: Another side of immune checkpoint. (PMID:36535461)
• Increased co-expression of stromal HHLA2 and fibroblast activation protein in upper tract urothelial carcinoma. (PMID:36598731)
• Immunosuppression by Inflammation-Stimulated Amplification of Myeloid-Derived Suppressor Cells and Changes in Expression of Immune Checkpoint HHLA2 in Chronic Obstructive Pulmonary Disease. (PMID:36846109)
• Overexpression and Role of HHLA2, a Novel Immune Checkpoint, in Colorectal Cancer. (PMID:36982953)
• HHLA2 immune-regulatory roles in cancer. (PMID:37011487)

Cross-species orthologs

0 orthologs

Paralogs (15): BTN3A1 (ENSG00000026950), CD276 (ENSG00000103855), BTN3A3 (ENSG00000111801), BTN2A1 (ENSG00000112763), BTNL8 (ENSG00000113303), BTN2A2 (ENSG00000124508), BTN1A1 (ENSG00000124557), VTCN1 (ENSG00000134258), ICOSLG (ENSG00000160223), ERMAP (ENSG00000164010), BTNL9 (ENSG00000165810), BTNL3 (ENSG00000168903), BTN3A2 (ENSG00000186470), BTNL2 (ENSG00000204290), MOG (ENSG00000204655)

Protein

Protein identifiers

HERV-H LTR-associating protein 2 — Q9UM44 (reviewed: Q9UM44)

Alternative names: Human endogenous retrovirus-H long terminal repeat-associating protein 2

All UniProt accessions (6): C9J7D0, C9JD07, C9JY13, C9JY43, Q9UM44, H7C523

UniProt curated annotations — full annotation on UniProt →

Function. Through interaction with TMIGD2, costimulates T-cells in the context of TCR-mediated activation. Enhances T-cell proliferation and cytokine production via an AKT-dependent signaling cascade.

Subunit / interactions. Interacts with TMIGD2.

Subcellular location. Membrane.

Tissue specificity. Expressed at high levels in colon, kidney, testis, lung and pancreas, and at lower levels in small intestine, liver and skeletal muscle. In immune cells, highly expressed in B-cells, dendritic cells and macrophages. Not detected in T-cells.

Induction. Up-regulated in antigen-presenting cells in response to inflammation. Induced in dendritic cells in response to IFNG, poly(I:C) or heat-killed Listeria monocytogenes (at protein level).

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UM44-1	1	yes
Q9UM44-2	2

RefSeq proteins (6): NP_001269485, NP_001269486, NP_001269487, NP_001269488, NP_001357173, NP_009003 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003597	Ig_C1-set	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050504	IgSF_BTN/MOG-like	Family

Pfam: PF07654, PF07686

UniProt features (16 total): sequence variant 3, domain 3, glycosylation site 3, disulfide bond 2, signal peptide 1, chain 1, splice variant 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UM44-F1	81.53	0.57

Functional residue map

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

Disulfide bonds (2): 159–210, 243–317

Glycosylation sites (3): 90, 103, 318

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 84 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_LYMPHOCYTE_COSTIMULATION, GOCC_CELL_SURFACE, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_CELL_CELL_ADHESION, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_LEUKOCYTE_PROLIFERATION, GOBP_CYTOKINE_PRODUCTION, GOBP_POSITIVE_REGULATION_OF_CELL_ACTIVATION, GOBP_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_ACTIVATED_T_CELL_PROLIFERATION

GO Biological Process (7): regulation of cytokine production (GO:0001817), positive regulation of cytokine production (GO:0001819), T cell costimulation (GO:0031295), positive regulation of activated T cell proliferation (GO:0042104), T cell receptor signaling pathway (GO:0050852), regulation of T cell activation (GO:0050863), regulation of leukocyte cell-cell adhesion (GO:1903037)

GO Molecular Function (2): signaling receptor binding (GO:0005102), protein binding (GO:0005515)

GO Cellular Component (3): external side of plasma membrane (GO:0009897), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytokine production	2
regulation of gene expression	1
regulation of multicellular organismal process	1
regulation of cytokine production	1
positive regulation of gene expression	1
positive regulation of multicellular organismal process	1
lymphocyte costimulation	1
positive regulation of T cell activation	1
positive regulation of T cell proliferation	1
regulation of activated T cell proliferation	1
activated T cell proliferation	1
antigen receptor-mediated signaling pathway	1
T cell activation	1
regulation of lymphocyte activation	1
leukocyte cell-cell adhesion	1
regulation of cell-cell adhesion	1
protein binding	1
binding	1
plasma membrane	1
cell surface	1
side of membrane	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

342 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HHLA2	ANKRD13C-DT	Q9XRX5	972
HHLA2	TMIGD2	Q96BF3	923
HHLA2	KIR3DL3	Q8N743	837
HHLA2	CTLA4	P16410	728
HHLA2	CD28	P10747	675
HHLA2	NCR3LG1	Q68D85	622
HHLA2	NCR3	O14931	607
HHLA2	PDCD1LG2	Q9BQ51	604
HHLA2	VSIR	Q9H7M9	600
HHLA2	TNFSF18	Q9UNG2	588
HHLA2	CD274	Q9NZQ7	581
HHLA2	CD8A	P01732	577
HHLA2	CD70	P32970	562
HHLA2	TNFSF9	P41273	558
HHLA2	BTLA	Q7Z6A9	535

IntAct

54 interactions, top by confidence:

A	B	Type	Score
SLC41A2	HHLA2	psi-mi:“MI:0915”(physical association)	0.560
SLC38A7	HHLA2	psi-mi:“MI:0915”(physical association)	0.560
RPRM	HHLA2	psi-mi:“MI:0915”(physical association)	0.560
FAM3C	HHLA2	psi-mi:“MI:0915”(physical association)	0.560
BTNL8	HHLA2	psi-mi:“MI:0915”(physical association)	0.560
BRICD5	HHLA2	psi-mi:“MI:0915”(physical association)	0.560
NIPAL4	HHLA2	psi-mi:“MI:0915”(physical association)	0.560
PGA4	HHLA2	psi-mi:“MI:0915”(physical association)	0.560
TTMP	HHLA2	psi-mi:“MI:0915”(physical association)	0.560
AQP9	HHLA2	psi-mi:“MI:0915”(physical association)	0.560
NRM	HHLA2	psi-mi:“MI:0915”(physical association)	0.560
SMCO4	HHLA2	psi-mi:“MI:0915”(physical association)	0.560
TNMD	HHLA2	psi-mi:“MI:0915”(physical association)	0.560
TMEM140	HHLA2	psi-mi:“MI:0915”(physical association)	0.560
UNC93B1	HHLA2	psi-mi:“MI:0915”(physical association)	0.560
ERMP1	HHLA2	psi-mi:“MI:0915”(physical association)	0.560
HHLA2	TMIGD2	psi-mi:“MI:0915”(physical association)	0.400
HHLA2	KIR3DL3	psi-mi:“MI:0915”(physical association)	0.400
TMIGD2	HHLA2	psi-mi:“MI:0915”(physical association)	0.400
KIR3DL3	HHLA2	psi-mi:“MI:0915”(physical association)	0.400
FAM3C	HHLA2	psi-mi:“MI:0915”(physical association)	0.000
NIPAL4	HHLA2	psi-mi:“MI:0915”(physical association)	0.000
PGA4	HHLA2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (14): HHLA2 (Two-hybrid), HHLA2 (Two-hybrid), HHLA2 (Two-hybrid), HHLA2 (Two-hybrid), HHLA2 (Two-hybrid), C3orf52 (Two-hybrid), NRM (Two-hybrid), TMEM140 (Two-hybrid), SMCO4 (Two-hybrid), NIPAL4 (Two-hybrid), RPRM (Two-hybrid), BRICD5 (Two-hybrid), FAM3C (Two-hybrid), PGA4 (Two-hybrid)

ESM2 similar proteins: A0A0E4BZH1, A7TZE6, A7TZF0, A7TZF3, A7TZG1, A7TZG3, A7XUX6, A7XV04, A7XV07, A7XV14, O54709, O70215, O95727, P0C1X9, P0DTI4, P26718, P42081, P61252, P83556, Q00609, Q29ZQ1, Q2YHT7, Q5RFR2, Q5UKY4, Q60651, Q60652, Q60654, Q60660, Q61885, Q63203, Q64329, Q68D85, Q6Q8B3, Q6XJV4, Q7Z6M3, Q8BG84, Q8BTP3, Q8MJH1, Q8TD46, Q921W8

Diamond homologs: A0A0E4BZH1, A4QPC6, A7TZE6, A7TZF0, A7TZF3, A7XUX6, A7XUY5, A7XUZ6, A7XV04, A7XV07, A8MVZ5, O00478, O00481, O70355, P18892, P55803, P78410, Q13410, Q16653, Q29ZQ1, Q5R7W8, Q5R960, Q5R996, Q5ZPR3, Q61885, Q62556, Q63345, Q68EV1, Q6MG97, Q6UX41, Q6UXE8, Q6UXG8, Q7KYR7, Q7TPB4, Q7TST0, Q8BJE2, Q8VE98, Q8WVV5, Q96KV6, Q96PL5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	52
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1758 predictions. Top by Δscore:

Variant	Effect	Δscore
3:108351787:GCAT:G	acceptor_gain	1.0000
3:108355113:A:AG	acceptor_gain	1.0000
3:108355114:G:GG	acceptor_gain	1.0000
3:108376491:A:AG	acceptor_gain	1.0000
3:108376492:G:C	acceptor_loss	1.0000
3:108376492:G:GA	acceptor_gain	1.0000
3:108376492:GAAA:G	acceptor_gain	1.0000
3:108296595:GTAAG:G	donor_gain	0.9900
3:108310654:GCAC:G	acceptor_gain	0.9900
3:108311755:A:AG	acceptor_gain	0.9900
3:108351786:A:AG	acceptor_gain	0.9900
3:108351787:G:GG	acceptor_gain	0.9900
3:108351787:GC:G	acceptor_gain	0.9900
3:108353426:GGCAT:G	acceptor_gain	0.9900
3:108353455:T:G	acceptor_gain	0.9900
3:108353551:G:GT	donor_gain	0.9900
3:108353778:GAGGT:G	donor_loss	0.9900
3:108353779:AGG:A	donor_loss	0.9900
3:108353780:GG:G	donor_loss	0.9900
3:108353782:T:A	donor_loss	0.9900
3:108355110:T:G	acceptor_gain	0.9900
3:108355114:GTTT:G	acceptor_gain	0.9900
3:108375882:G:GG	donor_gain	0.9900
3:108376492:GA:G	acceptor_gain	0.9900
3:108376492:GAA:G	acceptor_gain	0.9900
3:108376555:GTG:G	donor_gain	0.9900
3:108376558:GTAA:G	donor_loss	0.9900
3:108376559:TAA:T	donor_loss	0.9900
3:108296597:AAGGT:A	donor_loss	0.9800
3:108296599:GGT:G	donor_loss	0.9800

AlphaMissense

2742 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:108353549:T:A	W63R	0.954
3:108353549:T:C	W63R	0.954
3:108353551:G:C	W63C	0.953
3:108353551:G:T	W63C	0.953
3:108357936:T:A	W260R	0.946
3:108357936:T:C	W260R	0.946
3:108353519:T:C	F53L	0.942
3:108353521:T:A	F53L	0.942
3:108353521:T:G	F53L	0.942
3:108353717:T:G	Y119D	0.933
3:108353550:G:C	W63S	0.923
3:108358107:T:A	C317S	0.918
3:108358108:G:C	C317S	0.918
3:108353635:G:C	R91S	0.908
3:108353635:G:T	R91S	0.908
3:108353544:T:A	I61K	0.907
3:108358101:T:G	Y315D	0.906
3:108358102:A:C	Y315S	0.906
3:108353769:T:C	L136P	0.899
3:108353725:C:G	C121W	0.895
3:108357938:G:C	W260C	0.894
3:108357938:G:T	W260C	0.894
3:108353667:G:T	G102V	0.887
3:108358107:T:C	C317R	0.887
3:108353673:C:A	A104E	0.881
3:108355369:T:A	W225R	0.875
3:108355369:T:C	W225R	0.875
3:108355212:G:C	W172C	0.873
3:108355212:G:T	W172C	0.873
3:108353508:T:A	L49H	0.870

dbSNP variants (sampled 300 via entrez): RS1000020648 (3:108307755 C>T), RS1000086970 (3:108346005 C>T), RS1000109916 (3:108377105 A>G), RS1000134351 (3:108298952 C>T), RS1000193117 (3:108360216 A>G), RS1000193390 (3:108351341 T>C), RS1000223071 (3:108350908 C>T), RS1000224068 (3:108360564 C>G), RS1000295337 (3:108305612 A>G), RS1000361990 (3:108337145 A>G), RS1000418752 (3:108299194 A>T), RS1000472171 (3:108344217 A>T), RS1000508331 (3:108371289 C>A), RS1000537733 (3:108371468 T>C), RS1000609441 (3:108325279 G>A)

Disease associations

OMIM: gene MIM:604371 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006922_10	Regular attendance at a religious group	8.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009592	social interaction measurement

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
bisphenol A	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
(+)-JQ1 compound	decreases expression	1
Zoledronic Acid	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Estradiol	increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Lipopolysaccharides	increases expression, affects response to substance, affects cotreatment	1
Methyl Methanesulfonate	decreases expression	1
Smoke	increases abundance, increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	decreases methylation	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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