Is BIRC6 p.Leu1982Arg (c.5945T>G) pathogenic?

BIRC6 p.Leu1982Arg (c.5945T>G) is classified Uncertain significance in BIRC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-12). AlphaMissense: ambiguous (0.5319); Very rare (popmax 0.000509%, nfe).

How common is BIRC6 p.Leu1982Arg (c.5945T>G) in the general population?

BIRC6 p.Leu1982Arg (c.5945T>G) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about BIRC6 p.Leu1982Arg (c.5945T>G)?

AlphaMissense predicts ambiguous (score 0.5319) — an in-silico prediction, not a clinical call.

BIRC6 p.Leu1982Arg

c.5945T>G · VCV4828557

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5319 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5319	ambiguous
REVEL	0.493	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 69 kb · p 0.5 · regional, not allelic
Overall
CADD	24.5	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 0.000509% European (non-Finnish) · 6/1,179,900 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,908 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: BIRC6
Protein: p.Leu1982Arg
Coding: c.5945T>G
MANE Select: NM_016252
Type: single nucleotide variant
Location: chr2:32468601 (GRCh38)
Gene constraint: LOEUF 0.213 · pLI 1.00 (gnomAD)
Residue 1982: an α-helix

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-leu1982arg (accessed [today's date]).

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