CD96

Chr 3AD

CD96 molecule

Also known as: TACTILE

NCBI Gene: 10225 ENSG00000153283 UniProt: P40200 OMIM: 606037

CD96 encodes a type I membrane protein of the immunoglobulin superfamily that mediates adhesive interactions between activated T and NK cells and their targets during immune responses, particularly by binding to PVR on target cells. Mutations cause C syndrome with autosomal dominant inheritance. The gene shows minimal constraint against loss-of-function variants, suggesting the clinical phenotype may not result from simple protein loss.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to the immunoglobulin superfamily. It is a type I membrane protein. The protein may play a role in the adhesive interactions of activated T and NK cells during the late phase of the immune response. It may also function in antigen presentation. Alternative splicing generates multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2016]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.971 OMIM phenotype

Clinical Summary— CD96

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Gene-Disease Validity (ClinGen)

C syndrome · ADLimited

Limited evidence — not for standalone diagnostic reporting

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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

4 unique Pathogenic / Likely Pathogenic· 145 VUS of 197 total submissions

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Clinical Trials

11 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.97LOEUF

pLI 0.000

Z-score 1.69

OE 0.68 (0.48–0.97)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.47Z-score

OE missense 1.08 (0.98–1.18)

329 obs / 306.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.68 (0.48–0.97)

0≤0.351.4

Missense OE?1.08 (0.98–1.18)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 22 / 32.4Missense obs/exp: 329 / 306.0Syn Z: -1.21

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedCD96-related C syndromeLOFAD

This gene — mechanism propensity

0.6746th %ile

GOF

0.72top 25%

LOF

0.2969th %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

197 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic4

VUS145

Likely Benign31

Conflicting3

Likely Pathogenic

145

VUS

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	4	0	0	0	4
VUS	6	132	7	0	145
Likely Benign	0	9	10	12	31
Benign	0	0	0	0	0
Conflicting	—				3
Total	10	141	17	12	183

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

View in ClinVar →

2 pathogenic / likely-pathogenic (of 3) ClinVar copy-number / structural variants overlap CD96 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →