Is WAS p.Arg86His (c.257G>A) pathogenic?

WAS p.Arg86His (c.257G>A) is classified Pathogenic in WAS (ClinVar, Multiple submitters, 11 submitters; last evaluated 2025-07-01). AlphaMissense: ambiguous (0.4579); Very rare (popmax 0.000112%, nfe); Associated with WAS-related disorder.

What condition is associated with WAS p.Arg86His (c.257G>A)?

WAS p.Arg86His (c.257G>A) is associated with WAS-related disorder, X-linked severe congenital neutropenia, Wiskott-Aldrich syndrome (ClinVar).

How common is WAS p.Arg86His (c.257G>A) in the general population?

WAS p.Arg86His (c.257G>A) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about WAS p.Arg86His (c.257G>A)?

AlphaMissense predicts ambiguous (score 0.4579) — an in-silico prediction, not a clinical call.

WAS p.Arg86His

c.257G>A · rs132630268 · VCV11115

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

ambiguous

0.4579 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

WAS-related disorder

Computational evidence

Protein change
AlphaMissense	0.4579	ambiguous
REVEL	0.916	moderately pathogenic-leaning
SaProt	LLR -14.76	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 0.52	unconstrained · MANE · 1,973 bp · p 1.3e-07 · regional, not allelic
Overall
CADD	27.4	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 0.000112% European (non-Finnish) · 1/893,715 alleles

Overall 8.28e-05% 1/1,207,400 alleles · very rare exomes 1/1,095,144 · genomes 0/112,256 · joint denominator

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.Arg86His
Coding: c.257G>A
MANE Select: NM_000377
dbSNP: rs132630268
Type: single nucleotide variant
Location: chrX:48684407 (GRCh38)
Structure: AlphaFold pLDDT 70.84 · 7 PDB
Residue 86: the wh1 domain; a UniProt-annotated variant site (in was)

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

Disease context

Also linked: X-linked severe congenital neutropenia Wiskott-Aldrich syndrome thrombocytopenia 1

Similar variants

WAS p.Arg86Cys Pathogenic ★★ same residue
WAS p.Arg86Pro Likely pathogenic ★ same residue
WAS p.Arg86Leu Pathogenic same residue
WAS p.Arg86fs Pathogenic/Likely pathogenic ★★ same residue
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

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-arg86his (accessed [today's date]).

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