Is BLK p.Ile308Val (c.922A>G) pathogenic?

BLK p.Ile308Val (c.922A>G) is classified Conflicting classifications of pathogenicity in BLK (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-07). AlphaMissense: likely benign (0.1041); Ultra-rare (popmax 0.0986%, afr); Associated with maturity-onset diabetes of the young type 11.

What condition is associated with BLK p.Ile308Val (c.922A>G)?

BLK p.Ile308Val (c.922A>G) is associated with maturity-onset diabetes of the young type 11 (ClinVar).

How common is BLK p.Ile308Val (c.922A>G) in the general population?

BLK p.Ile308Val (c.922A>G) is ultra-rare (popmax 0.0986%, afr) (gnomAD).

How is MODY inherited?

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

What do computational predictors say about BLK p.Ile308Val (c.922A>G)?

AlphaMissense predicts likely benign (score 0.1041) — an in-silico prediction, not a clinical call.

BLK p.Ile308Val

c.922A>G · rs138547659 · VCV2428755

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1041 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0986%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

maturity-onset diabetes of the young type 11

Computational evidence

Protein change
AlphaMissense	0.1041	likely benign
REVEL	0.552	indeterminate
SaProt	LLR -9.17	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 21 kb · p 7e-14 · regional, not allelic
Overall
CADD	25.9	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 0.0986% African / African-American · 74/75,046 alleles

Filtering AF 0.0805% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0738%

Overall 0.0103% 167/1,614,174 alleles · ultra-rare exomes 93/1,461,854 · genomes 74/152,320 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0986%	1,014
Admixed American	0.05%	2,001
Remaining individualsnot grpmax-eligible	0.0128%	7,814
European (non-Finnish)	0.00466%	21,455

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.Ile308Val
Coding: c.922A>G
MANE Select: NM_001715
dbSNP: rs138547659
Type: single nucleotide variant
Location: chr8:11556807 (GRCh38)
Gene constraint: LOEUF 1.295 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.89
Residue 308: the protein kinase domain

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.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
BLK p.Ile338Thr Uncertain significance ★★ ⚠ same condition
BLK p.Leu381Ser 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-ile308val (accessed [today's date]).

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