IGSF6

Summary

IGSF6 (immunoglobulin superfamily member 6, HGNC:5953) is a protein-coding gene on chromosome 16p12.2, encoding Immunoglobulin superfamily member 6 (O95976).

Predicted to enable transmembrane signaling receptor activity. Predicted to be involved in cell surface receptor signaling pathway and immune response. Predicted to be located in plasma membrane.

Source: NCBI Gene 10261 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 131 total — 47 pathogenic
• MANE Select transcript: NM_005849

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5953
Approved symbol	IGSF6
Name	immunoglobulin superfamily member 6
Location	16p12.2
Locus type	gene with protein product
Status	Approved
Aliases	DORA
Ensembl gene	ENSG00000140749
Ensembl biotype	protein_coding
OMIM	606222
Entrez	10261

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000268389, ENST00000565499, ENST00000569602, ENST00000873899, ENST00000873900

RefSeq mRNA: 1 — MANE Select: NM_005849 NM_005849

CCDS: CCDS10599

Canonical transcript exons

ENST00000268389 — 6 exons

Exon	Start	End
ENSE00000944830	21647133	21647492
ENSE00000944832	21643548	21643598
ENSE00000944833	21643074	21643154
ENSE00000944834	21639550	21641593
ENSE00001949223	21652532	21652608
ENSE00003791560	21644290	21644396

Expression profiles

Bgee: expression breadth ubiquitous, 135 present calls, max score 98.07.

FANTOM5 (CAGE): breadth broad, TPM avg 34.8436 / max 1297.2939, expressed in 418 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
156735	30.1218	410
156736	4.7218	268

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	98.07	gold quality
leukocyte	CL:0000738	97.86	gold quality
blood	UBERON:0000178	95.86	gold quality
granulocyte	CL:0000094	92.49	gold quality
vermiform appendix	UBERON:0001154	91.06	gold quality
spleen	UBERON:0002106	88.09	gold quality
lymph node	UBERON:0000029	86.44	gold quality
bone marrow cell	CL:0002092	85.53	gold quality
bone marrow	UBERON:0002371	82.31	gold quality
placenta	UBERON:0001987	79.48	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.43	gold quality
rectum	UBERON:0001052	79.19	gold quality
gall bladder	UBERON:0002110	77.51	gold quality
lung	UBERON:0002048	76.84	gold quality
upper lobe of left lung	UBERON:0008952	76.19	gold quality
duodenum	UBERON:0002114	75.50	gold quality
adrenal tissue	UBERON:0018303	74.75	gold quality
smooth muscle tissue	UBERON:0001135	73.60	gold quality
tonsil	UBERON:0002372	73.35	gold quality
right coronary artery	UBERON:0001625	72.76	gold quality
corpus callosum	UBERON:0002336	72.70	gold quality
endometrium	UBERON:0001295	72.49	gold quality
liver	UBERON:0002107	72.11	gold quality
calcaneal tendon	UBERON:0003701	71.78	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	71.04	gold quality
right lung	UBERON:0002167	70.87	gold quality
stromal cell of endometrium	CL:0002255	70.52	gold quality
colonic epithelium	UBERON:0000397	69.31	gold quality
urinary bladder	UBERON:0001255	68.59	gold quality
adrenal gland	UBERON:0002369	68.32	gold quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 17.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	97.63
E-CURD-122	yes	48.32
E-CURD-46	yes	33.64
E-CURD-112	yes	27.92
E-MTAB-10287	yes	27.28
E-HCAD-10	yes	26.68
E-MTAB-9221	yes	26.61
E-MTAB-6701	yes	24.94
E-MTAB-10553	yes	22.26
E-CURD-88	yes	19.59
E-MTAB-10042	yes	17.99
E-GEOD-130148	yes	17.93
E-ANND-3	yes	17.42
E-MTAB-8410	yes	14.14
E-MTAB-9067	yes	12.62

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CD40LG

miRNA regulators (miRDB)

21 targeting IGSF6, 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-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4470	99.66	69.35	1767
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-6839-3P	99.39	68.86	1301
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-5190	99.15	67.76	1234
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-1248	98.47	67.54	1314
HSA-MIR-1912-5P	97.94	67.98	832
HSA-MIR-6890-3P	97.50	65.71	997
HSA-MIR-617	96.79	65.96	738
HSA-MIR-10525-3P	96.32	68.04	699
HSA-MIR-571	95.38	66.54	671

Literature-anchored findings (GeneRIF, showing 2)

• There was no evidence for association of the common IGSF6 single nucleotide polymorphisms with disease in a large cohort of patients with inflammatory bowel disease (PMID:12786995)
• Immunoglobulin superfamily 6 is a molecule involved in the anti-tumor activity of macrophages in lung adenocarcinoma. (PMID:38037023)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:ch211-139g16.8	ENSDARG00000093074
mus_musculus	Igsf6	ENSMUSG00000035004
rattus_norvegicus	Igsf6	ENSRNOG00000017277

Protein

Protein identifiers

Immunoglobulin superfamily member 6 — O95976 (reviewed: O95976)

Alternative names: Protein DORA

All UniProt accessions (2): O95976, H3BNM0

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Membrane.

Tissue specificity. Expressed in peripheral blood lymphocytes, spleen and lymph node, with low levels in thymus, bone marrow and fetal liver. No expression in non-immune tissues.

Induction. By TNF and CSF2/GM-CSF in dendritic cells and down regulation by phorbol myristate acetate (PMA) and ionomycin in monocytes.

Miscellaneous. This gene is localized to a locus associated with inflammatory bowel disease. It is coded entirely within the intron of METTL9 which is transcribed in the opposite strand of the DNA.

RefSeq proteins (1): NP_005840* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR039089	IGSF6	Family

Pfam: PF07686

UniProt features (13 total): sequence variant 3, topological domain 2, signal peptide 1, chain 1, sequence conflict 1, transmembrane region 1, domain 1, region of interest 1, compositionally biased region 1, disulfide bond 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95976-F1	79.03	0.47

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 (1): 51–118

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 189 (showing top): MODULE_45, MODULE_64, WIELAND_UP_BY_HBV_INFECTION, MODULE_75, GNF2_MCL1, GNF2_CD1D, FOSTER_TOLERANT_MACROPHAGE_DN, BLALOCK_ALZHEIMERS_DISEASE_UP, GNF2_S100A4, GNF2_HCK, DODD_NASOPHARYNGEAL_CARCINOMA_UP, AACTTT_UNKNOWN, WANG_IMMORTALIZED_BY_HOXA9_AND_MEIS1_UP, MODULE_46, LIAN_LIPA_TARGETS_3M

GO Biological Process (2): immune response (GO:0006955), cell surface receptor signaling pathway (GO:0007166)

GO Molecular Function (1): transmembrane signaling receptor activity (GO:0004888)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
immune system process	1
response to stimulus	1
signal transduction	1
signaling receptor activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1232 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IGSF6	METTL9	Q9H1A3	972
IGSF6	ITGAX	P20702	506
IGSF6	HCK	P08631	468
IGSF6	OTOA	Q7RTW8	466
IGSF6	CD40	P25942	449
IGSF6	CD40LG	P29965	434
IGSF6	ADGRE1	Q14246	413
IGSF6	IGSF22	Q8N9C0	398
IGSF6	WDR38	Q5JTN6	396
IGSF6	KNOP1	Q1ED39	393
IGSF6	MNDA	P41218	391
IGSF6	CD34	P28906	390
IGSF6	SASH3	O75995	382
IGSF6	RASAL3	Q86YV0	376
IGSF6	CTSS	P25774	375

IntAct

4 interactions, top by confidence:

A	B	Type	Score
IGSF6	CETN3	psi-mi:“MI:0914”(association)	0.530
IGSF6	lipA	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (14): GNPTAB (Affinity Capture-MS), RANGRF (Affinity Capture-MS), AP3S1 (Affinity Capture-MS), CWC27 (Affinity Capture-MS), CETN3 (Affinity Capture-MS), CANX (Affinity Capture-MS), IGSF6 (Synthetic Lethality), RANGRF (Affinity Capture-MS), CETN3 (Affinity Capture-MS), CWC27 (Affinity Capture-MS), GNPTAB (Affinity Capture-MS), UFSP2 (Affinity Capture-MS), AP3S1 (Affinity Capture-MS), APP (Reconstituted Complex)

ESM2 similar proteins: A0JM41, A2VD98, A6QQC6, A8MVW5, B0CLX4, B6ZK76, B6ZK77, O60487, O70255, O88324, O88775, O95976, P01832, P03228, P06907, P08920, P08921, P09619, P0C6B7, P0C6N0, P0CW72, P10522, P20938, P21995, P25189, P27573, P37301, P37998, P59823, P59824, P86176, Q01151, Q4VAH7, Q5EAB0, Q5R804, Q640U3, Q6PCB8, Q6WEB5, Q80UL9, Q86XK7

Diamond homologs: O95976, P0C6B7, Q9Z0K5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CD40LG	“down-regulates quantity by repression”	IGSF6	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	47
Likely pathogenic	0
Uncertain significance	62
Likely benign	5
Benign	8

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
3063400	GRCh37/hg19 16p12.2(chr16:21576802-21852932)x1	Pathogenic
3063403	GRCh37/hg19 16p12.2(chr16:21585791-21841354)x1	Pathogenic
3906909	GRCh37/hg19 16p12.2(chr16:21596300-21739821)x1	Pathogenic
634823	NC_000016.9:g.(21575218_21624036)_(21747738_21777910)del	Pathogenic
684885	GRCh37/hg19 16p12.2(chr16:21597346-21741439)x1	Pathogenic
684936	GRCh37/hg19 16p12.2(chr16:21585362-21745083)x1	Pathogenic
685072	GRCh37/hg19 16p12.2(chr16:21573708-21741439)x1	Pathogenic
685087	GRCh37/hg19 16p12.2(chr16:21597346-21741439)x1	Pathogenic
685124	GRCh37/hg19 16p12.2(chr16:21597346-21741439)x1	Pathogenic
685162	GRCh37/hg19 16p12.2(chr16:21618158-21852932)x1	Pathogenic
685248	GRCh37/hg19 16p12.2(chr16:21597346-21741439)x1	Pathogenic
685297	GRCh37/hg19 16p12.2(chr16:21597346-21741439)x1	Pathogenic
685313	GRCh37/hg19 16p12.2(chr16:21596299-21741439)x1	Pathogenic
685360	GRCh37/hg19 16p12.2(chr16:21545601-21807834)x1	Pathogenic
685648	GRCh37/hg19 16p12.2(chr16:21597346-21741439)x1	Pathogenic
685779	GRCh37/hg19 16p12.2(chr16:21597346-21741439)x1	Pathogenic
685824	GRCh37/hg19 16p12.2(chr16:21597346-21741439)x1	Pathogenic
686173	GRCh37/hg19 16p12.2(chr16:21597346-21741439)x1	Pathogenic
686198	GRCh37/hg19 16p12.2(chr16:21596299-21741439)x1	Pathogenic
686213	GRCh37/hg19 16p12.2(chr16:21597346-21741439)x1	Pathogenic
686322	GRCh37/hg19 16p12.2(chr16:21509521-21762200)x1	Pathogenic
686323	GRCh37/hg19 16p12.2(chr16:21597346-21741439)x1	Pathogenic
686460	GRCh37/hg19 16p12.2(chr16:21597346-21741439)x1	Pathogenic
686645	GRCh37/hg19 16p12.2(chr16:21596299-21741439)x1	Pathogenic
686778	GRCh37/hg19 16p12.2(chr16:21586020-21741439)x1	Pathogenic
686782	GRCh37/hg19 16p12.2(chr16:21597346-21741439)x1	Pathogenic
686784	GRCh37/hg19 16p12.2(chr16:21597346-21741439)x1	Pathogenic
686787	GRCh37/hg19 16p12.2(chr16:21586020-21741439)x1	Pathogenic
686837	GRCh37/hg19 16p12.2(chr16:21597346-21741439)x1	Pathogenic
686841	GRCh37/hg19 16p12.2(chr16:21597346-21741439)x1	Pathogenic

SpliceAI

853 predictions. Top by Δscore:

Variant	Effect	Δscore
16:21643072:A:AC	donor_gain	1.0000
16:21643073:C:CC	donor_gain	1.0000
16:21643073:CAGA:C	donor_gain	1.0000
16:21644283:GACTT:G	donor_loss	1.0000
16:21644284:ACTT:A	donor_loss	1.0000
16:21644285:CT:C	donor_loss	1.0000
16:21644286:TT:T	donor_loss	1.0000
16:21644287:TA:T	donor_loss	1.0000
16:21644288:A:AC	donor_gain	1.0000
16:21644288:AC:A	donor_loss	1.0000
16:21644289:C:CC	donor_gain	1.0000
16:21644289:C:CT	donor_loss	1.0000
16:21644289:CT:C	donor_gain	1.0000
16:21644394:TTT:T	acceptor_gain	1.0000
16:21644395:TT:T	acceptor_gain	1.0000
16:21644397:C:CC	acceptor_gain	1.0000
16:21644398:T:C	acceptor_gain	1.0000
16:21644398:T:TC	acceptor_gain	1.0000
16:21644401:A:AC	acceptor_gain	1.0000
16:21644401:A:C	acceptor_gain	1.0000
16:21644405:C:CT	acceptor_gain	1.0000
16:21644406:A:T	acceptor_gain	1.0000
16:21643073:CAG:C	donor_gain	0.9900
16:21643152:CTT:C	acceptor_gain	0.9900
16:21643155:C:CC	acceptor_gain	0.9900
16:21643599:C:CC	acceptor_gain	0.9900
16:21644289:CTT:C	donor_gain	0.9900
16:21644289:CTTTG:C	donor_gain	0.9900
16:21644392:AATTT:A	acceptor_gain	0.9900
16:21644393:ATTT:A	acceptor_gain	0.9900

AlphaMissense

1563 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:21647359:C:A	W67C	0.989
16:21647359:C:G	W67C	0.989
16:21647361:A:G	W67R	0.987
16:21647361:A:T	W67R	0.987
16:21647290:G:C	F90L	0.984
16:21647290:G:T	F90L	0.984
16:21647292:A:G	F90L	0.984
16:21647207:C:G	C118S	0.978
16:21647208:A:T	C118S	0.978
16:21647252:A:G	L103P	0.978
16:21647220:C:G	A114P	0.977
16:21647354:C:G	R69P	0.976
16:21647356:A:C	F68L	0.976
16:21647356:A:T	F68L	0.976
16:21647358:A:G	F68L	0.976
16:21647214:A:C	Y116D	0.975
16:21647409:A:G	C51R	0.974
16:21647207:C:T	C118Y	0.973
16:21647225:T:A	D112V	0.973
16:21647208:A:G	C118R	0.972
16:21647408:C:G	C51S	0.971
16:21647409:A:T	C51S	0.971
16:21647252:A:T	L103H	0.970
16:21647357:A:C	F68C	0.969
16:21647144:A:G	L139P	0.968
16:21647226:C:G	D112H	0.968
16:21643131:A:C	F203L	0.967
16:21643131:A:T	F203L	0.967
16:21643133:A:G	F203L	0.967
16:21647221:A:C	S113R	0.967

dbSNP variants (sampled 300 via entrez): RS1000074434 (16:21651162 G>T), RS1000353048 (16:21645206 A>G), RS1000364239 (16:21640839 A>G), RS1000371358 (16:21648367 C>T), RS1000422104 (16:21647954 C>T), RS1000719192 (16:21641184 G>A), RS1000909482 (16:21653631 T>A), RS1000953483 (16:21643298 C>G), RS1001071319 (16:21649593 G>T), RS1001082661 (16:21649866 G>A), RS1001300606 (16:21642910 T>C), RS1001594052 (16:21654167 A>G), RS1001617665 (16:21646587 T>A,G), RS1001697670 (16:21647239 T>C), RS1001735121 (16:21652428 T>A,C)

Disease associations

OMIM: gene MIM:606222 | disease phenotypes: MIM:601071

GenCC curated gene-disease

Mondo (1): autosomal recessive nonsyndromic hearing loss 9 (MONDO:0010986)

Orphanet (1): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005411_7	Thrombin-activatable fibrinolysis inhibitor activation peptide	5.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Nickel	decreases expression, increases expression	3
Benzo(a)pyrene	affects expression, decreases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation, decreases methylation	1
testosterone undecanoate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
Resveratrol	increases expression, affects cotreatment	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Acetaminophen	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	affects expression	1
Cadmium	decreases expression, increases abundance	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1
Tretinoin	increases expression	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Lactic Acid	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT05402813	Not specified	RECRUITING	Natural History in Children up to 16 Years With Mild to Profound Hearing Loss Due to Mutations in GJB2 / OTOF Genes
NCT05901480	Not specified	UNKNOWN	An Investigator Initiated Study for OTOV101N+OTOV101C Injection
NCT06722170	Not specified	RECRUITING	A Study of EH002 Gene Therapy for Otoferlin Gene Mutation-mediated Hearing Loss