Is CD276 p.Val425Ile (c.1273G>A) pathogenic?

CD276 p.Val425Ile (c.1273G>A) is classified Uncertain significance in CD276 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely benign (0.0696); Ultra-rare (popmax 0.0439%, sas).

How common is CD276 p.Val425Ile (c.1273G>A) in the general population?

CD276 p.Val425Ile (c.1273G>A) is ultra-rare (popmax 0.0439%, sas) (gnomAD).

What do computational predictors say about CD276 p.Val425Ile (c.1273G>A)?

AlphaMissense predicts likely benign (score 0.0696) — an in-silico prediction, not a clinical call.

CD276 p.Val425Ile

c.1273G>A · rs147409005 · VCV2592295

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0696 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0439%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0696	likely benign
REVEL	0.322	indeterminate
SaProt	LLR 0.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.28, phastCons 0.99
Regional constraint	o/e 0.88	unconstrained · MANE · 13 kb · p 0.0018 · regional, not allelic
Overall
CADD	20.7	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 0.0439% South Asian · 40/91,072 alleles

Filtering AF 0.0331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0293%

Overall 0.00917% 148/1,614,004 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0439%	2,277
Middle Eastern	0.0166%	6,022
African / African-American	0.0133%	7,501
East Asian	0.0111%	8,975
Admixed American	0.00999%	10,006
Remaining individualsnot grpmax-eligible	0.0096%	10,416
European (non-Finnish)	0.00678%	14,750

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.Val425Ile
Coding: c.1273G>A
MANE Select: NM_001024736
dbSNP: rs147409005
Type: single nucleotide variant
Location: chr15:73704376 (GRCh38)
Gene constraint: LOEUF 0.888 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.63 · 3 PDB
Residue 425: a disulfide bond; the ig-like c2-type 2 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-val425ile (accessed [today's date]).

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