Is BLNK p.Arg372Trp (c.1114C>T) pathogenic?

BLNK p.Arg372Trp (c.1114C>T) is classified Uncertain significance in BLNK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-05-06). AlphaMissense: likely pathogenic (0.9955); Very rare (popmax 0.00224%, eas); Associated with agammaglobulinemia 4, autosomal recessive.

What condition is associated with BLNK p.Arg372Trp (c.1114C>T)?

BLNK p.Arg372Trp (c.1114C>T) is associated with agammaglobulinemia 4, autosomal recessive (ClinVar).

How common is BLNK p.Arg372Trp (c.1114C>T) in the general population?

BLNK p.Arg372Trp (c.1114C>T) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about BLNK p.Arg372Trp (c.1114C>T)?

AlphaMissense predicts likely pathogenic (score 0.9955) — an in-silico prediction, not a clinical call.

BLNK p.Arg372Trp

c.1114C>T · rs782566012 · VCV439435

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9955 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

agammaglobulinemia 4, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.9955	likely pathogenic · top 2% in BLNK
REVEL	0.945	strongly pathogenic-leaning
SaProt	LLR -13.57	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.69 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 9,018 bp · p 3.7e-06 · regional, not allelic
Overall
CADD	25.8	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 0.00224% East Asian · 1/44,716 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000411% 6/1,460,086 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,716
Remaining individualsnot grpmax-eligible	0.0016%	62,438
Finnishnot grpmax-eligible	0.00157%	63,750
European (non-Finnish)	0.000254%	393,040

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: BLNK
Protein: p.Arg372Trp
Coding: c.1114C>T
MANE Select: NM_013314
dbSNP: rs782566012
Type: single nucleotide variant
Location: chr10:96197045 (GRCh38)
Gene constraint: LOEUF 0.517 · pLI 0.90 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.46 · 1 PDB
Residue 372: the sh2 domain

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

Disease context

agammaglobulinemia 4, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BLNK p.Arg372Gln Uncertain significance ★ ⚠ same residue
BLNK c.902+2T>C Likely pathogenic ★★ same condition
BLNK p.Ala176Val Uncertain significance ★★ ⚠ same condition
BLNK p.Ala218Thr Uncertain significance ★★ ⚠ same condition
BLNK p.Ala290Val Uncertain significance ★★ ⚠ same condition
BLNK p.Ala88Ser Uncertain significance ★★ ⚠ same condition
BLNK p.Ala92Asp Uncertain significance ★★ ⚠ same condition
BLNK p.Ala92Thr 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/blnk-p-arg372trp (accessed [today's date]).

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