Is WAS p.Val141Met (c.421G>A) pathogenic?

WAS p.Val141Met (c.421G>A) is classified Uncertain significance in WAS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-13). AlphaMissense: ambiguous (0.4067); Very rare (popmax 0.00239%, amr); Associated with X-linked severe congenital neutropenia.

What condition is associated with WAS p.Val141Met (c.421G>A)?

WAS p.Val141Met (c.421G>A) is associated with X-linked severe congenital neutropenia, Wiskott-Aldrich syndrome, thrombocytopenia 1 (ClinVar).

How common is WAS p.Val141Met (c.421G>A) in the general population?

WAS p.Val141Met (c.421G>A) is very rare (popmax 0.00239%, amr) (gnomAD).

How is X-linked severe congenital neutropenia inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about WAS p.Val141Met (c.421G>A)?

AlphaMissense predicts ambiguous (score 0.4067) — an in-silico prediction, not a clinical call.

WAS p.Val141Met

c.421G>A · VCV3762991

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4067 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00239%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

X-linked severe congenital neutropenia

Computational evidence

Protein change
AlphaMissense	0.4067	ambiguous
REVEL	0.726	pathogenic-leaning
SaProt	LLR -7.53	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.52	unconstrained · MANE · 1,973 bp · p 1.3e-07 · regional, not allelic
Overall
CADD	24.3	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 0.00239% Admixed American · 1/41,802 alleles

Filtering AF 3.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000253% 3/1,186,345 alleles · very rare exomes 3/1,072,767 · genomes 0/113,578 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00239%	41,802
European (non-Finnish)	0.000227%	441,184

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: WAS
Protein: p.Val141Met
Coding: c.421G>A
MANE Select: NM_000377
Type: single nucleotide variant
Location: chrX:48685794 (GRCh38)
Structure: AlphaFold pLDDT 70.84 · 7 PDB
Residue 141: the wh1 domain

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

Disease context

X-linked severe congenital neutropenia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Wiskott-Aldrich syndrome thrombocytopenia 1

For X-linked severe congenital neutropenia (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy, Neonatal

Similar variants

WAS c.1339-2A>G Pathogenic/Likely pathogenic ★★ same condition
WAS c.1453+2T>C Pathogenic ★★ same condition
WAS c.273+1G>A Pathogenic ★★ same condition
WAS c.360+1G>A Pathogenic ★★ same condition
WAS c.559+5G>A Pathogenic ★★ same condition
WAS c.777+1G>A Pathogenic ★★ same condition
WAS c.778-6G>A Pathogenic ★★ same condition
WAS p.Ala56Val Pathogenic ★★ 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/was-p-val141met (accessed [today's date]).

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