Is BLK p.Ala403Val (c.1208C>T) pathogenic?

BLK p.Ala403Val (c.1208C>T) is classified Uncertain significance in BLK (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely pathogenic (0.9781); Very rare (popmax 8.47e-05%, nfe); Associated with maturity-onset diabetes of the young type 11.

What condition is associated with BLK p.Ala403Val (c.1208C>T)?

BLK p.Ala403Val (c.1208C>T) is associated with maturity-onset diabetes of the young type 11 (ClinVar).

How common is BLK p.Ala403Val (c.1208C>T) in the general population?

BLK p.Ala403Val (c.1208C>T) is very rare (popmax 8.47e-05%, nfe) (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.Ala403Val (c.1208C>T)?

AlphaMissense predicts likely pathogenic (score 0.9781) — an in-silico prediction, not a clinical call.

BLK p.Ala403Val

c.1208C>T · rs139210041 · VCV361494

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9781 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

maturity-onset diabetes of the young type 11

Computational evidence

Protein change
AlphaMissense	0.9781	likely pathogenic · top 9% in BLK
REVEL	0.623	indeterminate
SaProt	LLR -15.57	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 21 kb · p 7e-14 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,020 alleles

Overall 6.2e-05% 1/1,614,134 alleles · very rare exomes 1/1,461,778 · genomes 0/152,356 · 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.Ala403Val
Coding: c.1208C>T
MANE Select: NM_001715
dbSNP: rs139210041
Type: single nucleotide variant
Location: chr8:11563006 (GRCh38)
Gene constraint: LOEUF 1.295 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.89
Residue 403: 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.Ala403= Likely benign ★ 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
BLK p.Ile338Thr 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-ala403val (accessed [today's date]).

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