Is BLK p.Pro225= (c.675G>A) pathogenic?

BLK p.Pro225= (c.675G>A) is classified Likely benign in BLK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-03). Ultra-rare (popmax 0.02%, afr); Associated with maturity-onset diabetes of the young type 11.

What condition is associated with BLK p.Pro225= (c.675G>A)?

BLK p.Pro225= (c.675G>A) is associated with maturity-onset diabetes of the young type 11 (ClinVar).

How common is BLK p.Pro225= (c.675G>A) in the general population?

BLK p.Pro225= (c.675G>A) is ultra-rare (popmax 0.02%, afr) (gnomAD).

How is MODY inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

BLK p.Pro225=

c.675G>A · rs761122806 · VCV1653759

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, afr)

Conditions

maturity-onset diabetes of the young type 11

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP -3.7	GERP -3.9
Overall
CADD	1.25	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% African / African-American · 15/74,902 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00989%

Overall 0.00335% 54/1,613,994 alleles · ultra-rare exomes 44/1,461,866 · genomes 10/152,128 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.02%	4,993
East Asian	0.00891%	11,222
South Asian	0.00549%	18,215
Admixed American	0.005%	20,001
European (non-Finnish)	0.0022%	45,386
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Pro225=
Coding: c.675G>A
MANE Select: NM_001715
dbSNP: rs761122806
Type: single nucleotide variant
Location: chr8:11555387 (GRCh38)
Gene constraint: LOEUF 1.295 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.89

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

Disease context

maturity-onset diabetes of the young type 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MODY (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

BLK p.Pro225Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
BLK p.Pro225Gln Uncertain significance ★★ ⚠ same residue
BLK p.Arg180His Uncertain significance ★★ ⚠ same condition
BLK p.Arg295Trp Uncertain significance ★★ same condition
BLK p.Arg298Gln Uncertain significance ★★ ⚠ same condition
BLK p.Gln226Pro Uncertain significance ★★ ⚠ same condition
BLK p.Gly451Ser Uncertain significance ★★ ⚠ same condition
BLK p.His55Arg Uncertain significance ★★ ⚠ same condition

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-pro225 (accessed [today's date]).

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