Is BLNK p.Leu15Phe (c.45G>C) pathogenic?

BLNK p.Leu15Phe (c.45G>C) is classified Uncertain significance in BLNK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-03). AlphaMissense: ambiguous (0.377); Ultra-rare (popmax 0.0374%, afr); Associated with agammaglobulinemia 4, autosomal recessive.

What condition is associated with BLNK p.Leu15Phe (c.45G>C)?

BLNK p.Leu15Phe (c.45G>C) is associated with agammaglobulinemia 4, autosomal recessive (ClinVar).

How common is BLNK p.Leu15Phe (c.45G>C) in the general population?

BLNK p.Leu15Phe (c.45G>C) is ultra-rare (popmax 0.0374%, afr) (gnomAD).

What do computational predictors say about BLNK p.Leu15Phe (c.45G>C)?

AlphaMissense predicts ambiguous (score 0.377) — an in-silico prediction, not a clinical call.

BLNK p.Leu15Phe

c.45G>C · rs138255946 · VCV837684

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.377 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0374%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

agammaglobulinemia 4, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.377	ambiguous
REVEL	0.094	moderately benign-leaning
SaProt	LLR -7.05	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 0.97, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 47 kb · p 0.00042 · regional, not allelic
Overall
CADD	21.4	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 0.0374% African / African-American · 28/74,942 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0229%

Overall 0.00186% 30/1,614,044 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0374%	2,677
Admixed American	0.00167%	60,006
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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.Leu15Phe
Coding: c.45G>C
MANE Select: NM_013314
dbSNP: rs138255946
Type: single nucleotide variant
Location: chr10:96271354 (GRCh38)
Gene constraint: LOEUF 0.517 · pLI 0.90 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.46 · 1 PDB

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 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-leu15phe (accessed [today's date]).

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