Is BIRC2 p.Leu254Pro (c.761T>C) pathogenic?

BIRC2 p.Leu254Pro (c.761T>C) is classified Uncertain significance in BIRC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely benign (0.0787); Very rare (popmax 0.00533%, afr).

How common is BIRC2 p.Leu254Pro (c.761T>C) in the general population?

BIRC2 p.Leu254Pro (c.761T>C) is very rare (popmax 0.00533%, afr) (gnomAD).

What do computational predictors say about BIRC2 p.Leu254Pro (c.761T>C)?

AlphaMissense predicts likely benign (score 0.0787) — an in-silico prediction, not a clinical call.

BIRC2 p.Leu254Pro

c.761T>C · VCV4209319

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0787 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0787	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -5.92	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 0.97	GERP 0.63, phastCons 0.006
Regional constraint	o/e 1.02	unconstrained · MANE · 1,007 bp · p 0.63 · regional, not allelic
Overall
CADD	17.93	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 0.00533% African / African-American · 4/75,042 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00041% 6/1,461,876 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00533%	18,760
Remaining individualsnot grpmax-eligible	0.0016%	62,512
European (non-Finnish)	8.47e-05%	1,180,036

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: BIRC2
Protein: p.Leu254Pro
Coding: c.761T>C
MANE Select: NM_001166
Type: single nucleotide variant
Location: chr11:102350615 (GRCh38)
Gene constraint: LOEUF 0.381 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.08 · 29 PDB

Full BIRC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BIRC2 p.Ala506Val Benign ★★ same type
BIRC2 p.Ala186Thr Uncertain significance ★ ⚠ same type
BIRC2 p.Ala388Thr Uncertain significance ★ ⚠ same type
BIRC2 p.Ala58Ser Uncertain significance ★ ⚠ same type
BIRC2 p.Arg164Lys Uncertain significance ★ ⚠ same type
BIRC2 p.Arg241Gln Uncertain significance ★ ⚠ same type
BIRC2 p.Arg300Cys Uncertain significance ★ ⚠ same type
BIRC2 p.Arg338Gln 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/birc2-p-leu254pro (accessed [today's date]).

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