Is BLK p.Phe112Ser (c.335T>C) pathogenic?

BLK p.Phe112Ser (c.335T>C) is classified Benign/Likely benign in BLK (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-05-01). AlphaMissense: likely pathogenic (0.6117); Low-frequency (popmax 1.76%, afr); Associated with monogenic diabetes.

What condition is associated with BLK p.Phe112Ser (c.335T>C)?

BLK p.Phe112Ser (c.335T>C) is associated with monogenic diabetes (ClinVar).

How common is BLK p.Phe112Ser (c.335T>C) in the general population?

BLK p.Phe112Ser (c.335T>C) is low-frequency (popmax 1.76%, afr) (gnomAD).

What do computational predictors say about BLK p.Phe112Ser (c.335T>C)?

AlphaMissense predicts likely pathogenic (score 0.6117) — an in-silico prediction, not a clinical call.

BLK p.Phe112Ser

c.335T>C · rs115068920 · VCV393411

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.6117 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.76%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

monogenic diabetes

Computational evidence

Protein change
AlphaMissense	0.6117	likely pathogenic
REVEL	0.252	benign-leaning
SaProt	LLR -9.59	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 1.7	GERP -1.8, phastCons 0.99
Regional constraint	o/e 1.29	unconstrained · MANE · 21 kb · p 7e-14 · regional, not allelic
Overall
CADD	25.2	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 1.76% African / African-American · 1,316/74,970 alleles

Filtering AF 1.68% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.64%

Overall 0.0927% 1,493/1,610,566 alleles · low-frequency exomes 764/1,458,316 · genomes 729/152,250 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.76%	57
Middle Eastern	0.182%	551
Remaining individualsnot grpmax-eligible	0.117%	855
Admixed American	0.101%	993
European (non-Finnish)	0.00263%	38,022
South Asian	0.00223%	44,848

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.Phe112Ser
Coding: c.335T>C
MANE Select: NM_001715
dbSNP: rs115068920
Type: single nucleotide variant
Location: chr8:11549089 (GRCh38)
Gene constraint: LOEUF 1.295 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.89
Residue 112: the sh3 domain

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

Disease context

monogenic diabetes — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BLK p.Phe112= Likely benign ★ same residue
BLK p.Arg238Trp Uncertain significance ★★ ⚠ same condition
BLK p.Pro52Thr Uncertain significance ★★ ⚠ same condition
BLK p.Trp23Arg Uncertain significance ★★ ⚠ same condition
BLK p.Ala71Thr Benign/Likely benign ★★ same condition
BLK p.Arg238Gln Benign/Likely benign ★★ same condition
BLK p.Asp59Glu Benign/Likely benign ★★ same condition
BLK p.Arg131Gly 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-phe112ser (accessed [today's date]).

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