Is BIRC3 p.Arg135Cys (c.403C>T) pathogenic?

BIRC3 p.Arg135Cys (c.403C>T) is classified Uncertain significance in BIRC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-13). AlphaMissense: likely benign (0.077); Rare (popmax 0.225%, eas).

How common is BIRC3 p.Arg135Cys (c.403C>T) in the general population?

BIRC3 p.Arg135Cys (c.403C>T) is rare (popmax 0.225%, eas) (gnomAD).

What do computational predictors say about BIRC3 p.Arg135Cys (c.403C>T)?

AlphaMissense predicts likely benign (score 0.077) — an in-silico prediction, not a clinical call.

BIRC3 p.Arg135Cys

c.403C>T · rs200590873 · VCV2227710

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.077 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.225%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.077	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -7.80	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 4.8	GERP -3.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 1,023 bp · p 0.056 · regional, not allelic
Overall
CADD	18.47	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 0.225% East Asian · 101/44,888 alleles

Filtering AF 0.189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.176%

Overall 0.00638% 103/1,614,154 alleles · rare exomes 98/1,461,878 · genomes 5/152,276 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.225%	444
Admixed American	0.00333%	30,008

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.Arg135Cys
Coding: c.403C>T
MANE Select: NM_001165
dbSNP: rs200590873
Type: single nucleotide variant
Location: chr11:102324912 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 75.13 · 6 PDB

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-arg135cys (accessed [today's date]).

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