Is BIRC3 p.Arg332Cys (c.994C>T) pathogenic?

BIRC3 p.Arg332Cys (c.994C>T) is classified Uncertain significance in BIRC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: likely benign (0.0774); Ultra-rare (popmax 0.0764%, amr).

How common is BIRC3 p.Arg332Cys (c.994C>T) in the general population?

BIRC3 p.Arg332Cys (c.994C>T) is ultra-rare (popmax 0.0764%, amr) (gnomAD).

What do computational predictors say about BIRC3 p.Arg332Cys (c.994C>T)?

AlphaMissense predicts likely benign (score 0.0774) — an in-silico prediction, not a clinical call.

BIRC3 p.Arg332Cys

c.994C>T · rs200082566 · VCV2343724

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0774 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0764%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0774	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -8.88	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 0.81	GERP -3.7
Regional constraint	o/e 1.05	unconstrained · MANE · 8,854 bp · p 0.44 · regional, not allelic
Overall
CADD	19.33	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 0.0764% Admixed American · 45/58,886 alleles

Filtering AF 0.0586% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0524%

Overall 0.00516% 83/1,609,034 alleles · ultra-rare exomes 65/1,456,942 · genomes 18/152,092 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0764%	1,309
African / African-American	0.0174%	5,733
Ashkenazi Jewishnot grpmax-eligible	0.00678%	14,752
Remaining individualsnot grpmax-eligible	0.00321%	31,145
European (non-Finnish)	0.0017%	58,923
South Asian	0.00111%	89,832

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: BIRC3
Protein: p.Arg332Cys
Coding: c.994C>T
MANE Select: NM_001165
dbSNP: rs200082566
Type: single nucleotide variant
Location: chr11:102328092 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 75.13 · 6 PDB
Residue 332: an α-helix

Full BIRC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BIRC3 p.Arg332His Uncertain significance ★ ⚠ same residue
BIRC3 p.Arg401Lys Likely benign ★★ same type
BIRC3 p.Arg555= Benign ★★ same type
BIRC3 p.Lys87= Benign ★★ same type
BIRC3 p.Asp530His Likely pathogenic ★ ⚠ same type
BIRC3 p.Cys557Ter Likely pathogenic ★ same type
BIRC3 p.Cys588Tyr Likely pathogenic ★ same type
BIRC3 p.His312Tyr Likely pathogenic ★ 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/birc3-p-arg332cys (accessed [today's date]).

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