WASHC5

Chr 8ARAD

WASH complex subunit 5

Also known as: KIAA0196, RTSC, RTSC1, SPG8

NCBI Gene: 9897 ENSG00000164961 UniProt: Q12768 OMIM: 610657

The protein strumpellin acts as a component of the WASH core complex that recruits and activates the Arp2/3 complex to induce actin polymerization at endosome surfaces, playing a key role in endosome sorting and cellular trafficking. Mutations cause either autosomal dominant spastic paraplegia 8 characterized by progressive lower extremity spasticity, or autosomal recessive Ritscher-Schinzel syndrome 1 which involves multiple organ systems. This gene is highly intolerant to loss-of-function variants (pLI ~0), indicating it is under strong evolutionary constraint.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a 134 kDa protein named strumpellin that is predicted to have multiple transmembrane domains and a spectrin-repeat-containing domain. This ubiquitously expressed gene has its highest expression in skeletal muscle. The protein is named for Strumpell disease; a form of hereditary spastic paraplegia (HSP). Spastic paraplegias are a diverse group of disorders in which the autosomal dominant forms are characterized by progressive, lower extremity spasticity caused by axonal degeneration in the terminal portions of the longest descending and ascending corticospinal tracts. More than 30 loci (SPG1-33) have been implicated in hereditary spastic paraplegia diseases. [provided by RefSeq, Aug 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAR/ADLOEUF 0.742 OMIM phenotypes

Clinical Summary— WASHC5

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Gene-Disease Validity (ClinGen)

hereditary spastic paraplegia 8 · ADModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

46 unique Pathogenic / Likely Pathogenic· 324 VUS of 795 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — WASHC5

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.74LOEUF

pLI 0.000

Z-score 3.29

OE 0.57 (0.44–0.74)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.30Z-score

OE missense 0.85 (0.79–0.92)

527 obs / 617.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.57 (0.44–0.74)

0≤0.351.4

Missense OE?0.85 (0.79–0.92)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 39 / 68.3Missense obs/exp: 527 / 617.6Syn Z: -0.46

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongWASHC5-related intellectual disability, congenital cardiac malformation, and Dandy-Walker malformationLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6454th %ile

GOF

0.6833th %ile

LOF

0.3067th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

795 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19

Likely Pathogenic27

VUS324

Likely Benign195

Benign156

Conflicting38

Pathogenic

Likely Pathogenic

324

VUS

195

Likely Benign

156

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	14	5	0	0	19
Likely Pathogenic	18	7	2	0	27
VUS	12	256	46	10	324
Likely Benign	0	3	96	96	195
Benign	0	3	148	5	156
Conflicting	—				38
Total	44	274	292	111	759

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

54 pathogenic / likely-pathogenic (of 66) ClinVar copy-number / structural variants overlap WASHC5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →