Is CD226 p.Val79Ala (c.236T>C) pathogenic?

CD226 p.Val79Ala (c.236T>C) is classified Uncertain significance in CD226 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: ambiguous (0.3635); Very rare (popmax 0.00329%, sas).

How common is CD226 p.Val79Ala (c.236T>C) in the general population?

CD226 p.Val79Ala (c.236T>C) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about CD226 p.Val79Ala (c.236T>C)?

AlphaMissense predicts ambiguous (score 0.3635) — an in-silico prediction, not a clinical call.

CD226 p.Val79Ala

c.236T>C · VCV4222725

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3635 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3635	ambiguous
REVEL	0.283	benign-leaning
SaProt	LLR -7.89	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	phastCons 0.97
Regional constraint	o/e 0.96	unconstrained · MANE · 83 kb · p 0.44 · regional, not allelic
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,078 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000248% 4/1,613,932 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,359
European (non-Finnish)	8.47e-05%	1,180,012

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: CD226
Protein: p.Val79Ala
Coding: c.236T>C
MANE Select: NM_001303618
Type: single nucleotide variant
Location: chr18:69946880 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.75 · 2 PDB
Residue 79: a disulfide bond; the ig-like c2-type 1 domain

Full CD226 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD226 p.Ala133Val Uncertain significance ★ ⚠ same type
CD226 p.Ala16Gly Uncertain significance ★ ⚠ same type
CD226 p.Ala226Thr Uncertain significance ★ ⚠ same type
CD226 p.Ala76Thr Uncertain significance ★ ⚠ same type
CD226 p.Ala76Val Uncertain significance ★ ⚠ same type
CD226 p.Ala9Pro Uncertain significance ★ ⚠ same type
CD226 p.Arg193Gly Uncertain significance ★ ⚠ same type
CD226 p.Asn198Thr 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/cd226-p-val79ala (accessed [today's date]).

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