Is BLK p.Arg192fs (c.574dup) pathogenic?

BLK p.Arg192fs (c.574dup) is classified Uncertain significance in BLK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). Ultra-rare (popmax 0.0166%, mid).

How common is BLK p.Arg192fs (c.574dup) in the general population?

BLK p.Arg192fs (c.574dup) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

BLK p.Arg192fs

c.574dup · VCV4698883

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP 0.9, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,034 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00329%

Overall 0.00372% 60/1,613,474 alleles · ultra-rare exomes 59/1,461,674 · genomes 1/151,800 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,034
European (non-Finnish)	0.00466%	21,453
Remaining individualsnot grpmax-eligible	0.0032%	31,244
Finnishnot grpmax-eligible	0.00157%	63,850
African / African-American	0.00134%	74,864

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.Arg192fs
Coding: c.574dup
MANE Select: NM_001715
Type: Duplication
Location: chr8:11554838 (GRCh38)
Gene constraint: LOEUF 1.295 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.89
Residue 192: the sh2 domain

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

Similar variants

BLK p.Arg192Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
BLK p.Arg238fs Uncertain significance ★ same type
BLK p.Glu478fs Uncertain significance ★ same type
BLK p.Glu83fs 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-arg192fs (accessed [today's date]).

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