Is BIRC2 p.Arg338Gly (c.1012C>G) pathogenic?

BIRC2 p.Arg338Gly (c.1012C>G) is classified Uncertain significance in BIRC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-18). AlphaMissense: likely benign (0.1607); Very rare (popmax 0.00204%, nfe).

How common is BIRC2 p.Arg338Gly (c.1012C>G) in the general population?

BIRC2 p.Arg338Gly (c.1012C>G) is very rare (popmax 0.00204%, nfe) (gnomAD).

What do computational predictors say about BIRC2 p.Arg338Gly (c.1012C>G)?

AlphaMissense predicts likely benign (score 0.1607) — an in-silico prediction, not a clinical call.

BIRC2 p.Arg338Gly

c.1012C>G · rs896200881 · VCV2328007

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1607 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00204%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1607	likely benign
REVEL	0.161	moderately benign-leaning
SaProt	LLR -9.54	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 0.44	GERP -0.95, phastCons 0.93
Regional constraint	o/e 0.56	unconstrained · MANE · 13 kb · p 0.00023 · regional, not allelic
Overall
CADD	21.7	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 0.00204% European (non-Finnish) · 24/1,178,834 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00149% 24/1,612,098 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.Arg338Gly
Coding: c.1012C>G
MANE Select: NM_001166
dbSNP: rs896200881
Type: single nucleotide variant
Location: chr11:102362912 (GRCh38)
Gene constraint: LOEUF 0.381 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.08 · 29 PDB
Residue 338: an α-helix

Full BIRC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BIRC2 p.Arg338Gln 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-arg338gly (accessed [today's date]).

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