Is WAS p.Pro460Ser (c.1378C>T) pathogenic?

WAS p.Pro460Ser (c.1378C>T) is classified Benign in WAS (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.067); Low-frequency (popmax 2.93%, eas); Associated with thrombocytopenia 1.

What condition is associated with WAS p.Pro460Ser (c.1378C>T)?

WAS p.Pro460Ser (c.1378C>T) is associated with thrombocytopenia 1, X-linked severe congenital neutropenia, Wiskott-Aldrich syndrome (ClinVar).

How common is WAS p.Pro460Ser (c.1378C>T) in the general population?

WAS p.Pro460Ser (c.1378C>T) is low-frequency (popmax 2.93%, eas) (gnomAD).

What do computational predictors say about WAS p.Pro460Ser (c.1378C>T)?

AlphaMissense predicts likely benign (score 0.067) — an in-silico prediction, not a clinical call.

WAS p.Pro460Ser

c.1378C>T · rs143885622 · VCV135411

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.067 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.93%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombocytopenia 1

Computational evidence

Protein change
AlphaMissense	0.067	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -6.77	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 0.39	GERP 0.26
Regional constraint	o/e 0.90	unconstrained · MANE · 2,456 bp · p 0.22 · regional, not allelic
Overall
CADD	14.01	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 2.93% East Asian · 986/33,672 alleles

Filtering AF 2.78% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.72%

Overall 0.202% 2,438/1,207,556 alleles · low-frequency exomes 2,241/1,096,125 · genomes 197/111,431 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	2.93%	34
Ashkenazi Jewishnot grpmax-eligible	0.269%	372
Remaining individualsnot grpmax-eligible	0.206%	485
European (non-Finnish)	0.133%	750
South Asian	0.112%	891
Middle Eastern	0.0691%	1,448
Admixed American	0.0526%	1,899
Finnishnot grpmax-eligible	0.013%	7,721
African / African-American	0.0105%	9,505

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.Pro460Ser
Coding: c.1378C>T
MANE Select: NM_000377
dbSNP: rs143885622
Type: single nucleotide variant
Location: chrX:48689359 (GRCh38)
Structure: AlphaFold pLDDT 70.84 · 7 PDB
Residue 460: the 'disordered' region

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

Disease context

thrombocytopenia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

WAS p.Pro460Arg 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-pro460ser (accessed [today's date]).

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