Is BIRC3 p.Leu50Val (c.148C>G) pathogenic?

BIRC3 p.Leu50Val (c.148C>G) is classified Uncertain significance in BIRC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-19). AlphaMissense: ambiguous (0.4095); Very rare (popmax 0.000424%, nfe).

How common is BIRC3 p.Leu50Val (c.148C>G) in the general population?

BIRC3 p.Leu50Val (c.148C>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about BIRC3 p.Leu50Val (c.148C>G)?

AlphaMissense predicts ambiguous (score 0.4095) — an in-silico prediction, not a clinical call.

BIRC3 p.Leu50Val

c.148C>G · rs978016131 · VCV2328447

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4095 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4095	ambiguous
REVEL	0.82	moderately pathogenic-leaning
SaProt	LLR -10.70	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 1,023 bp · p 0.056 · regional, not allelic
Overall
CADD	24.8	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 0.000424% European (non-Finnish) · 5/1,180,024 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,184 alleles · very rare exomes 5/1,461,868 · genomes 0/152,316 · 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: BIRC3
Protein: p.Leu50Val
Coding: c.148C>G
MANE Select: NM_001165
dbSNP: rs978016131
Type: single nucleotide variant
Location: chr11:102324657 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 75.13 · 6 PDB
Residue 50: an α-helix

Full BIRC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BIRC3 p.Arg401Lys Likely benign ★★ same type
BIRC3 p.Arg555= Benign ★★ same type
BIRC3 p.Lys87= Benign ★★ same type
BIRC3 p.Asp530His Likely pathogenic ★ ⚠ same type
BIRC3 p.Cys557Ter Likely pathogenic ★ same type
BIRC3 p.Cys588Tyr Likely pathogenic ★ same type
BIRC3 p.His312Tyr Likely pathogenic ★ same type
BIRC3 p.Ter605Arg Likely pathogenic ★ 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/birc3-p-leu50val (accessed [today's date]).

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