Is BLNK p.Val435Ile (c.1303G>A) pathogenic?

BLNK p.Val435Ile (c.1303G>A) is classified Uncertain significance in BLNK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-25). AlphaMissense: likely benign (0.1186); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with BLNK p.Val435Ile (c.1303G>A)?

BLNK p.Val435Ile (c.1303G>A) is associated with Inborn genetic diseases, agammaglobulinemia 4, autosomal recessive (ClinVar).

How common is BLNK p.Val435Ile (c.1303G>A) in the general population?

BLNK p.Val435Ile (c.1303G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about BLNK p.Val435Ile (c.1303G>A)?

AlphaMissense predicts likely benign (score 0.1186) — an in-silico prediction, not a clinical call.

BLNK p.Val435Ile

c.1303G>A · rs138157505 · VCV2161874

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1186 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1186	likely benign
REVEL	0.171	moderately benign-leaning
SaProt	LLR -6.34	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP 0.031, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 9,018 bp · p 3.7e-06 · regional, not allelic
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0165% Middle Eastern · 1/6,076 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00372% 60/1,613,526 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,076
Remaining individualsnot grpmax-eligible	0.0048%	20,821
European (non-Finnish)	0.00441%	22,688
African / African-American	0.00401%	24,956
South Asian	0.0011%	91,080

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.Val435Ile
Coding: c.1303G>A
MANE Select: NM_013314
dbSNP: rs138157505
Type: single nucleotide variant
Location: chr10:96192041 (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 435: the sh2 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: agammaglobulinemia 4, autosomal recessive

Similar variants

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
BLNK p.Arg282Gln 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-val435ile (accessed [today's date]).

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