Is BIK p.Pro25Leu (c.74C>T) pathogenic?

BIK p.Pro25Leu (c.74C>T) is classified Likely benign in BIK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-29). AlphaMissense: likely benign (0.0732); Ultra-rare (popmax 0.0267%, amr).

How common is BIK p.Pro25Leu (c.74C>T) in the general population?

BIK p.Pro25Leu (c.74C>T) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about BIK p.Pro25Leu (c.74C>T)?

AlphaMissense predicts likely benign (score 0.0732) — an in-silico prediction, not a clinical call.

BIK p.Pro25Leu

c.74C>T · rs369306278 · VCV2291970

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0732 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0732	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -6.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.42	GERP -2.9
Regional constraint	o/e 1.03	unconstrained · MANE · 5,279 bp · p 0.62 · regional, not allelic
Overall
CADD	6.036	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 0.0267% Admixed American · 16/60,020 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00297% 48/1,614,162 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,751
South Asian	0.0176%	5,693
Remaining individualsnot grpmax-eligible	0.016%	6,251
East Asian	0.00223%	44,892
European (non-Finnish)	0.000424%	235,999

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: BIK
Protein: p.Pro25Leu
Coding: c.74C>T
MANE Select: NM_001197
dbSNP: rs369306278
Type: single nucleotide variant
Location: chr22:43124096 (GRCh38)
Gene constraint: LOEUF 1.838 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.38

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

Similar variants

BIK p.Ala56Thr Uncertain significance ★ ⚠ same type
BIK p.Arg60Gln Uncertain significance ★ ⚠ same type
BIK p.Asp99Asn Uncertain significance ★ ⚠ same type
BIK p.Glu134Lys Uncertain significance ★ ⚠ same type
BIK p.Glu98Gly Uncertain significance ★ ⚠ same type
BIK p.Gly154Asp Uncertain significance ★ ⚠ same type
BIK p.Gly154Ser Uncertain significance ★ ⚠ same type
BIK p.Leu104Pro Uncertain significance ★ ⚠ 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/bik-p-pro25leu (accessed [today's date]).

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