Is BIRC6 p.Arg3286Trp (c.9856C>T) pathogenic?

BIRC6 p.Arg3286Trp (c.9856C>T) is classified Uncertain significance in BIRC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-19). AlphaMissense: likely pathogenic (0.7372); Ultra-rare (popmax 0.0223%, eas).

How common is BIRC6 p.Arg3286Trp (c.9856C>T) in the general population?

BIRC6 p.Arg3286Trp (c.9856C>T) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about BIRC6 p.Arg3286Trp (c.9856C>T)?

AlphaMissense predicts likely pathogenic (score 0.7372) — an in-silico prediction, not a clinical call.

BIRC6 p.Arg3286Trp

c.9856C>T · rs372922939 · VCV3134105

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7372 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.7372	likely pathogenic
REVEL	0.8	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.2, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 1,745 bp · p 1.2e-05 · regional, not allelic
Overall
CADD	23.8	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0223% East Asian · 10/44,888 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00916%

Overall 0.00279% 45/1,613,726 alleles · ultra-rare exomes 40/1,461,698 · genomes 5/152,028 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,489
Admixed American	0.005%	19,997
Remaining individualsnot grpmax-eligible	0.0032%	31,228
European (non-Finnish)	0.00246%	40,686
African / African-American	0.00134%	74,844

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: BIRC6
Protein: p.Arg3286Trp
Coding: c.9856C>T
MANE Select: NM_016252
dbSNP: rs372922939
Type: single nucleotide variant
Location: chr2:32508135 (GRCh38)
Gene constraint: LOEUF 0.213 · pLI 1.00 (gnomAD)

Full BIRC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BIRC6 p.Arg3286Gln Uncertain significance ★ same residue
BIRC6 p.Gln853Arg Uncertain significance ★★ ⚠ same type
BIRC6 p.Glu4506Asp Uncertain significance ★★ ⚠ same type
BIRC6 c.7409-6T>C Likely benign ★★ same type
BIRC6 p.Ala1549= Benign ★★ same type
BIRC6 p.Ala3622Val Likely benign ★★ same type
BIRC6 p.Ala4466= Benign/Likely benign ★★ same type
BIRC6 p.Arg4605= Benign ★★ 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/birc6-p-arg3286trp (accessed [today's date]).

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