Is BLK p.Arg433Trp (c.1297C>T) pathogenic?

BLK p.Arg433Trp (c.1297C>T) is classified Uncertain significance in BLK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-27). AlphaMissense: likely benign (0.2773); Ultra-rare (popmax 0.0133%, amr).

How common is BLK p.Arg433Trp (c.1297C>T) in the general population?

BLK p.Arg433Trp (c.1297C>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about BLK p.Arg433Trp (c.1297C>T)?

AlphaMissense predicts likely benign (score 0.2773) — an in-silico prediction, not a clinical call.

BLK p.Arg433Trp

c.1297C>T · rs751422253 · VCV2183174

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2773 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2773	likely benign
REVEL	0.663	pathogenic-leaning
SaProt	LLR -13.13	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	Δ0.29	donor gain · deltas
Pangolin	Δ0.20	gain · loss 0.04 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.5	GERP 2, phastCons 0.99
Regional constraint	o/e 1.29	unconstrained · MANE · 21 kb · p 7e-14 · regional, not allelic
Overall
CADD	33.0	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 0.0133% Admixed American · 8/60,002 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.0039% 63/1,613,816 alleles · ultra-rare exomes 61/1,461,612 · genomes 2/152,204 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,500
European (non-Finnish)	0.00441%	22,693
Remaining individualsnot grpmax-eligible	0.0032%	31,241
East Asian	0.00223%	44,888

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: BLK
Protein: p.Arg433Trp
Coding: c.1297C>T
MANE Select: NM_001715
dbSNP: rs751422253
Type: single nucleotide variant
Location: chr8:11563095 (GRCh38)
Gene constraint: LOEUF 1.295 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.89
Residue 433: the protein kinase domain

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

Similar variants

BLK p.Arg131Gln Uncertain significance ★★ ⚠ same type
BLK p.Arg180His Uncertain significance ★★ ⚠ same type
BLK p.Arg238Trp Uncertain significance ★★ ⚠ same type
BLK p.Arg295Trp Uncertain significance ★★ same type
BLK p.Arg298Gln Uncertain significance ★★ ⚠ same type
BLK p.Arg466His Uncertain significance ★★ ⚠ same type
BLK p.Asp68Val Uncertain significance ★★ same type
BLK p.Gln226Pro 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/blk-p-arg433trp (accessed [today's date]).

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