IGSF8

Chr 1

immunoglobulin superfamily member 8

Also known as: CD316, CD81P3, EWI-2, EWI2, KCT-4, LIR-D1, PGRL

NCBI Gene: 93185 ENSG00000162729 UniProt: Q969P0

This gene encodes a member the EWI subfamily of the immunoglobulin protein superfamily. Members of this family contain a single transmembrane domain, an EWI (Glu-Trp-Ile)-motif and a variable number of immunoglobulin domains. This protein interacts with the tetraspanins CD81 and CD9 and may regulate their role in certain cellular functions including cell migration and viral infection. The encoded protein may also function as a tumor suppressor by inhibiting the proliferation of certain cancers. Alternate splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Sep 2011]

Research

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.05

Clinical Summary— IGSF8

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

107 VUS of 131 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.05LOEUF

pLI 0.000

Z-score 1.35

OE 0.72 (0.51–1.05)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.44Z-score

OE missense 0.94 (0.86–1.02)

377 obs / 401.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.72 (0.51–1.05)

0≤0.351.4

Missense OE?0.94 (0.86–1.02)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 20 / 27.6Missense obs/exp: 377 / 401.7Syn Z: 0.77

This gene — mechanism propensity

0.6550th %ile

GOF

0.7029th %ile

LOF

0.3549th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

131 submitted variants in ClinVar

ClinVar

Classification Summary

VUS107

Likely Benign1

Benign1

107

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	106	1	0	107
Likely Benign	0	0	1	1
Benign	0	0	1	1
Total	106	1	2	109

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

9 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap IGSF8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →