Is BIRC2 p.Met181Thr (c.542T>C) pathogenic?

BIRC2 p.Met181Thr (c.542T>C) is classified Uncertain significance in BIRC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-03). AlphaMissense: likely pathogenic (0.5811); Very rare (popmax 0.00167%, amr).

How common is BIRC2 p.Met181Thr (c.542T>C) in the general population?

BIRC2 p.Met181Thr (c.542T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about BIRC2 p.Met181Thr (c.542T>C)?

AlphaMissense predicts likely pathogenic (score 0.5811) — an in-silico prediction, not a clinical call.

BIRC2 p.Met181Thr

c.542T>C · rs1842770553 · VCV2293688

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5811 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5811	likely pathogenic
REVEL	0.524	indeterminate
SaProt	LLR -11.16	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 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 1,007 bp · p 0.63 · regional, not allelic
Overall
CADD	24.3	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 0.00167% Admixed American · 1/60,002 alleles

Overall 0.000657% 1/152,218 alleles · very rare

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.Met181Thr
Coding: c.542T>C
MANE Select: NM_001166
dbSNP: rs1842770553
Type: single nucleotide variant
Location: chr11:102350396 (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.Met181Lys Uncertain significance ★ ⚠ same residue
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

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-met181thr (accessed [today's date]).

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