Is CD276 p.Val124Met (c.370G>A) pathogenic?

CD276 p.Val124Met (c.370G>A) is classified Uncertain significance in CD276 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely pathogenic (0.6019); Ultra-rare (popmax 0.0334%, afr).

How common is CD276 p.Val124Met (c.370G>A) in the general population?

CD276 p.Val124Met (c.370G>A) is ultra-rare (popmax 0.0334%, afr) (gnomAD).

What do computational predictors say about CD276 p.Val124Met (c.370G>A)?

AlphaMissense predicts likely pathogenic (score 0.6019) — an in-silico prediction, not a clinical call.

CD276 p.Val124Met

c.370G>A · rs374277885 · VCV3140485

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6019 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6019	likely pathogenic
REVEL	0.236	benign-leaning
SaProt	LLR -14.86	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 0.26, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 13 kb · p 0.0018 · regional, not allelic
Overall
CADD	27.5	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 0.0334% African / African-American · 25/74,934 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0198%

Overall 0.00186% 30/1,611,734 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0334%	2,997
Admixed American	0.00333%	29,989
European (non-Finnish)	0.000254%	393,272

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: CD276
Protein: p.Val124Met
Coding: c.370G>A
MANE Select: NM_001024736
dbSNP: rs374277885
Type: single nucleotide variant
Location: chr15:73702545 (GRCh38)
Gene constraint: LOEUF 0.888 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.63 · 3 PDB
Residue 124: the ig-like v-type 1 domain

Full CD276 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD276 p.Leu419= Benign ★★ same type
CD276 p.Ala132Ser Uncertain significance ★ ⚠ same type
CD276 p.Ala139Ser Uncertain significance ★ ⚠ same type
CD276 p.Ala28Ser Uncertain significance ★ ⚠ same type
CD276 p.Ala312Thr Uncertain significance ★ ⚠ same type
CD276 p.Ala350Thr Uncertain significance ★ ⚠ same type
CD276 p.Ala351Val Uncertain significance ★ ⚠ same type
CD276 p.Ala432Gly 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/cd276-p-val124met (accessed [today's date]).

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