Is BIRC6 p.Glu4506Asp (c.13518A>C) pathogenic?

BIRC6 p.Glu4506Asp (c.13518A>C) is classified Uncertain significance in BIRC6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-10). AlphaMissense: likely benign (0.0762); Very rare (popmax 0.000256%, nfe); Associated with BIRC6-related disorder.

What condition is associated with BIRC6 p.Glu4506Asp (c.13518A>C)?

BIRC6 p.Glu4506Asp (c.13518A>C) is associated with BIRC6-related disorder (ClinVar).

How common is BIRC6 p.Glu4506Asp (c.13518A>C) in the general population?

BIRC6 p.Glu4506Asp (c.13518A>C) is very rare (popmax 0.000256%, nfe) (gnomAD).

What do computational predictors say about BIRC6 p.Glu4506Asp (c.13518A>C)?

AlphaMissense predicts likely benign (score 0.0762) — an in-silico prediction, not a clinical call.

BIRC6 p.Glu4506Asp

c.13518A>C · rs764484444 · VCV2631389

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0762 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000256%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

BIRC6-related disorder

Computational evidence

Protein change
AlphaMissense	0.0762	likely benign
REVEL	0.192	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -3.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 55 kb · p 4.9e-05 · regional, not allelic
Overall
CADD	18.36	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000256% European (non-Finnish) · 3/1,171,436 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000189% 3/1,589,642 alleles · very rare exomes 2/1,437,518 · genomes 1/152,124 · joint denominator

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.Glu4506Asp
Coding: c.13518A>C
MANE Select: NM_016252
dbSNP: rs764484444
Type: single nucleotide variant
Location: chr2:32595050 (GRCh38)
Gene constraint: LOEUF 0.213 · pLI 1.00 (gnomAD)

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

Disease context

BIRC6-related disorder

Similar variants

BIRC6 p.Gln853Arg Uncertain significance ★★ ⚠ same condition
BIRC6 p.Arg1075Gln Uncertain significance ★ ⚠ same condition
BIRC6 p.Asp386Glu Uncertain significance ★ same condition
BIRC6 p.Asp673His Uncertain significance ★ same condition
BIRC6 p.Ser1258Ala Uncertain significance ★ ⚠ same condition
BIRC6 p.Ser3427Phe Uncertain significance ★ same condition
BIRC6 p.Asp3819Tyr Uncertain significance same condition
BIRC6 p.His3051Leu Uncertain significance same condition

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-glu4506asp (accessed [today's date]).

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