Is BIRC3 p.Ile331Thr (c.992T>C) pathogenic?

BIRC3 p.Ile331Thr (c.992T>C) is classified Uncertain significance in BIRC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-27). AlphaMissense: ambiguous (0.4106); Very rare (popmax 0.00501%, nfe).

How common is BIRC3 p.Ile331Thr (c.992T>C) in the general population?

BIRC3 p.Ile331Thr (c.992T>C) is very rare (popmax 0.00501%, nfe) (gnomAD).

What do computational predictors say about BIRC3 p.Ile331Thr (c.992T>C)?

AlphaMissense predicts ambiguous (score 0.4106) — an in-silico prediction, not a clinical call.

BIRC3 p.Ile331Thr

c.992T>C · VCV3480691

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4106 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00501%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4106	ambiguous
REVEL	0.22	benign-leaning
SaProt	LLR -12.20	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.1	GERP 1.9, phastCons 0.98
Regional constraint	o/e 1.05	unconstrained · MANE · 8,854 bp · p 0.44 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00501% European (non-Finnish) · 59/1,178,792 alleles

Filtering AF 0.00394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00361%

Overall 0.00373% 60/1,609,828 alleles · very rare exomes 59/1,457,614 · genomes 1/152,214 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00501%	19,980
Remaining individualsnot grpmax-eligible	0.0016%	62,328

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.Ile331Thr
Coding: c.992T>C
MANE Select: NM_001165
Type: single nucleotide variant
Location: chr11:102328090 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 75.13 · 6 PDB
Residue 331: an α-helix

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

Similar variants

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
BIRC3 p.Ter605Arg 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-ile331thr (accessed [today's date]).

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