Is CD276 p.Leu136Pro (c.407T>C) pathogenic?

CD276 p.Leu136Pro (c.407T>C) is classified Uncertain significance in CD276 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-09). AlphaMissense: likely pathogenic (0.9849); Ultra-rare (popmax 0.0135%, nfe).

How common is CD276 p.Leu136Pro (c.407T>C) in the general population?

CD276 p.Leu136Pro (c.407T>C) is ultra-rare (popmax 0.0135%, nfe) (gnomAD).

What do computational predictors say about CD276 p.Leu136Pro (c.407T>C)?

AlphaMissense predicts likely pathogenic (score 0.9849) — an in-silico prediction, not a clinical call.

CD276 p.Leu136Pro

c.407T>C · VCV3829481

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9849 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0135%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9849	likely pathogenic · top 1% in CD276
REVEL	0.482	indeterminate
SaProt	LLR -13.17	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 13 kb · p 0.0018 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0135% European (non-Finnish) · 159/1,177,670 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0111%

Overall 0.0105% 168/1,607,056 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0135%	7,407
Remaining individualsnot grpmax-eligible	0.0112%	8,892
African / African-American	0.00267%	37,437

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.Leu136Pro
Coding: c.407T>C
MANE Select: NM_001024736
Type: single nucleotide variant
Location: chr15:73702582 (GRCh38)
Gene constraint: LOEUF 0.888 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.63 · 3 PDB
Residue 136: 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-leu136pro (accessed [today's date]).

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