Is WAS p.Ala433= (c.1299G>A) pathogenic?

WAS p.Ala433= (c.1299G>A) is classified Benign/Likely benign in WAS (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-28). Low-frequency (popmax 2.65%, sas); Associated with X-linked severe congenital neutropenia.

What condition is associated with WAS p.Ala433= (c.1299G>A)?

WAS p.Ala433= (c.1299G>A) is associated with X-linked severe congenital neutropenia, Wiskott-Aldrich syndrome, thrombocytopenia 1 (ClinVar).

How common is WAS p.Ala433= (c.1299G>A) in the general population?

WAS p.Ala433= (c.1299G>A) is low-frequency (popmax 2.65%, sas) (gnomAD).

How is X-linked severe congenital neutropenia inherited?

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

WAS p.Ala433=

c.1299G>A · rs372649110 · VCV212587

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.65%, sas)

Conditions

X-linked severe congenital neutropenia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -3.7
Overall
CADD	0.335	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.65% South Asian · 1,489/56,269 alleles

Filtering AF 2.53% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.49%

Overall 0.134% 1,617/1,203,318 alleles · low-frequency exomes 1,528/1,091,813 · genomes 89/111,505 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	2.65%	38
Remaining individualsnot grpmax-eligible	0.192%	522
Middle Eastern	0.0465%	2,149
African / African-American	0.0105%	9,513
East Asian	0.00891%	11,218
European (non-Finnish)	0.00291%	34,383

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.Ala433=
Coding: c.1299G>A
MANE Select: NM_000377
dbSNP: rs372649110
Type: single nucleotide variant
Location: chrX:48689027 (GRCh38)
Structure: AlphaFold pLDDT 70.84 · 7 PDB
Residue 433: an α-helix; the wh2 domain; the 'disordered' region

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 p.Ala433Val Uncertain significance ★ ⚠ 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
WAS c.559+5G>A Pathogenic ★★ same condition
WAS c.777+1G>A Pathogenic ★★ same condition
WAS c.778-6G>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-ala433 (accessed [today's date]).

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