Is CD96 p.Val61Ile (c.181G>A) pathogenic?

CD96 p.Val61Ile (c.181G>A) is classified Uncertain significance in CD96 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-18). AlphaMissense: likely benign (0.0797); Rare (popmax 0.66%, mid).

How common is CD96 p.Val61Ile (c.181G>A) in the general population?

CD96 p.Val61Ile (c.181G>A) is rare (popmax 0.66%, mid) (gnomAD).

What do computational predictors say about CD96 p.Val61Ile (c.181G>A)?

AlphaMissense predicts likely benign (score 0.0797) — an in-silico prediction, not a clinical call.

CD96 p.Val61Ile

c.181G>A · rs150450686 · VCV1524983

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0797 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.66%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0797	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -6.52	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.73	GERP -3.6
Regional constraint	o/e 1.10	unconstrained · MANE · 108 kb · p 0.013 · regional, not allelic
Overall
CADD	0.896	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.66% Middle Eastern · 40/6,062 alleles

Filtering AF 0.498% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.442%

Overall 0.0493% 796/1,614,122 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.66%	152
Admixed American	0.17%	588
Ashkenazi Jewishnot grpmax-eligible	0.115%	871
Remaining individualsnot grpmax-eligible	0.112%	893
South Asian	0.0461%	2,168
European (non-Finnish)	0.0425%	2,355
Finnishnot grpmax-eligible	0.00781%	12,802
African / African-American	0.00267%	37,514

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CD96
Protein: p.Val61Ile
Coding: c.181G>A
MANE Select: NM_005816
dbSNP: rs150450686
Type: single nucleotide variant
Location: chr3:111545165 (GRCh38)
Gene constraint: LOEUF 1.16 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.81 · 1 PDB
Residue 61: a disulfide bond; a β-strand; the ig-like v-type 1 domain

Full CD96 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD96 c.1249+1G>A Uncertain significance ★★ same type
CD96 c.544-1512C>T Uncertain significance ★★ ⚠ same type
CD96 p.Asp205Gly Uncertain significance ★★ ⚠ same type
CD96 p.Asp224Asn Uncertain significance ★★ ⚠ same type
CD96 p.Ile151Thr Uncertain significance ★★ ⚠ same type
CD96 p.Leu120Pro Uncertain significance ★★ ⚠ same type
CD96 p.Lys500Arg Uncertain significance ★★ ⚠ same type
CD96 p.Pro346Ser Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cd96-p-val61ile (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown