Is BIRC2 p.Met453Ile (c.1359G>A) pathogenic?

BIRC2 p.Met453Ile (c.1359G>A) is classified Uncertain significance in BIRC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely benign (0.106); Rare (popmax 0.954%, afr).

How common is BIRC2 p.Met453Ile (c.1359G>A) in the general population?

BIRC2 p.Met453Ile (c.1359G>A) is rare (popmax 0.954%, afr) (gnomAD).

What do computational predictors say about BIRC2 p.Met453Ile (c.1359G>A)?

AlphaMissense predicts likely benign (score 0.106) — an in-silico prediction, not a clinical call.

BIRC2 p.Met453Ile

c.1359G>A · VCV4209378

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.106 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.954%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.106	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -1.15	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 2	GERP 0.045, phastCons 0.98
Regional constraint	o/e 1.12	unconstrained · MANE · 14 kb · p 0.071 · regional, not allelic
Overall
CADD	14.95	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 0.954% African / African-American · 714/74,844 alleles

Filtering AF 0.896% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.873%

Overall 0.0518% 836/1,612,784 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.954%	105
Remaining individualsnot grpmax-eligible	0.114%	880
Admixed American	0.0635%	1,575
Middle Eastern	0.033%	3,029
South Asian	0.0044%	22,716
European (non-Finnish)	0.000593%	168,506

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.Met453Ile
Coding: c.1359G>A
MANE Select: NM_001166
Type: single nucleotide variant
Location: chr11:102368541 (GRCh38)
Gene constraint: LOEUF 0.381 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.08 · 29 PDB
Residue 453: a UniProt-annotated variant site (in); the card domain; an α-helix

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-met453ile (accessed [today's date]).

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