Is BIK p.Leu143Pro (c.428T>C) pathogenic?

BIK p.Leu143Pro (c.428T>C) is classified Uncertain significance in BIK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-09). AlphaMissense: likely benign (0.243); Very rare (popmax 0.00435%, nfe).

How common is BIK p.Leu143Pro (c.428T>C) in the general population?

BIK p.Leu143Pro (c.428T>C) is very rare (popmax 0.00435%, nfe) (gnomAD).

What do computational predictors say about BIK p.Leu143Pro (c.428T>C)?

AlphaMissense predicts likely benign (score 0.243) — an in-silico prediction, not a clinical call.

BIK p.Leu143Pro

c.428T>C · rs145876995 · VCV3133995

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.243 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00435%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.243	likely benign
REVEL	0.119	moderately benign-leaning
SaProt	LLR -6.19	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 3.1	GERP -0.76, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 5,279 bp · p 0.62 · regional, not allelic
Overall
CADD	18.07	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00435% European (non-Finnish) · 51/1,172,848 alleles

Filtering AF 0.00336% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00304%

Overall 0.00339% 54/1,591,198 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00435%	22,997
Ashkenazi Jewishnot grpmax-eligible	0.00347%	28,822
Remaining individualsnot grpmax-eligible	0.00324%	30,863

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.Leu143Pro
Coding: c.428T>C
MANE Select: NM_001197
dbSNP: rs145876995
Type: single nucleotide variant
Location: chr22:43129250 (GRCh38)
Gene constraint: LOEUF 1.838 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.38
Residue 143: the 'leucine-zipper' region

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-leu143pro (accessed [today's date]).

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