Is BIRC6 p.Arg3939Ser (c.11817G>T) pathogenic?

BIRC6 p.Arg3939Ser (c.11817G>T) is classified Uncertain significance in BIRC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-16). AlphaMissense: likely pathogenic (0.9964); Ultra-rare (popmax 0.0164%, mid).

How common is BIRC6 p.Arg3939Ser (c.11817G>T) in the general population?

BIRC6 p.Arg3939Ser (c.11817G>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about BIRC6 p.Arg3939Ser (c.11817G>T)?

AlphaMissense predicts likely pathogenic (score 0.9964) — an in-silico prediction, not a clinical call.

BIRC6 p.Arg3939Ser

c.11817G>T · VCV3260964

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9964 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Computational evidence

Protein change
AlphaMissense	0.9964	likely pathogenic · top 6% in BIRC6
REVEL	0.445	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -5, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 34 kb · p 0.095 · regional, not allelic
Overall
CADD	19.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00223% 36/1,613,826 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Admixed American	0.005%	19,997
European (non-Finnish)	0.00254%	39,329
Remaining individualsnot grpmax-eligible	0.0016%	62,458
South Asian	0.0011%	91,082

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.Arg3939Ser
Coding: c.11817G>T
MANE Select: NM_016252
Type: single nucleotide variant
Location: chr2:32525525 (GRCh38)
Gene constraint: LOEUF 0.213 · pLI 1.00 (gnomAD)
Residue 3939: the 'disordered' region; the ubiquitin-like domain

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

Similar variants

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
BIRC6 p.Asp4607= 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-arg3939ser (accessed [today's date]).

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