Is BLK p.Ser356Pro (c.1066T>C) pathogenic?

BLK p.Ser356Pro (c.1066T>C) is classified Uncertain significance in BLK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). AlphaMissense: likely pathogenic (0.9741); Ultra-rare (popmax 0.0165%, mid).

How common is BLK p.Ser356Pro (c.1066T>C) in the general population?

BLK p.Ser356Pro (c.1066T>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about BLK p.Ser356Pro (c.1066T>C)?

AlphaMissense predicts likely pathogenic (score 0.9741) — an in-silico prediction, not a clinical call.

BLK p.Ser356Pro

c.1066T>C · rs1801497643 · VCV2287156

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9741 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9741	likely pathogenic · top 10% in BLK
REVEL	0.253	benign-leaning
SaProt	LLR -8.83	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 21 kb · p 7e-14 · regional, not allelic
Overall
CADD	24.1	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 0.0165% Middle Eastern · 1/6,062 alleles

Overall 6.2e-05% 1/1,614,010 alleles · ultra-rare exomes 1/1,461,714 · genomes 0/152,296 · 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: BLK
Protein: p.Ser356Pro
Coding: c.1066T>C
MANE Select: NM_001715
dbSNP: rs1801497643
Type: single nucleotide variant
Location: chr8:11561338 (GRCh38)
Gene constraint: LOEUF 1.295 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.89
Residue 356: 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-ser356pro (accessed [today's date]).

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