WASHC5

Chr 8ARAD

WASH complex subunit 5

NCBI Gene: 9897ENSG00000164961UniProt: Q12768

Acts as a component of the WASH core complex that functions as a nucleation-promoting factor (NPF) at the surface of endosomes, where it recruits and activates the Arp2/3 complex to induce actin polymerization, playing a key role in the fission of tubules that serve as transport intermediates during endosome sorting (PubMed:19922875, PubMed:20498093). May be involved in axonal outgrowth. Involved in cellular localization of ADRB2 (PubMed:23085491). Involved in cellular trafficking of BLOC-1 complex cargos such as ATP7A and VAMP7 (PubMed:23676666)

Primary Disease Associations & Inheritance

Ritscher-Schinzel syndrome 1MIM #220210
AR
Spastic paraplegia 8, autosomal dominantMIM #603563
AD
563
ClinVar variants
43
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— WASHC5
🧬
Gene-Disease Validity (ClinGen)
hereditary spastic paraplegia 8 · ADModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
43 Pathogenic / Likely Pathogenic· 258 VUS of 563 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.74LOEUF
pLI 0.000
Z-score 3.29
OE 0.57 (0.44–0.74)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.30Z-score
OE missense 0.85 (0.79–0.92)
527 obs / 617.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.57 (0.44–0.74)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.85 (0.79–0.92)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.04
0≤1.21.6
LoF obs/exp: 39 / 68.3Missense obs/exp: 527 / 617.6Syn Z: -0.46

ClinVar Variant Classifications

563 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27
Likely Pathogenic16
VUS258
Likely Benign135
Benign116
Conflicting11
27
Pathogenic
16
Likely Pathogenic
258
VUS
135
Likely Benign
116
Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
2
19
0
27
Likely Pathogenic
13
1
2
0
16
VUS
6
209
39
4
258
Likely Benign
0
0
75
60
135
Benign
0
0
116
0
116
Conflicting
—11
Total2521225164563

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

View in ClinVar →

Protein Context — Lollipop Plot

WASHC5 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

WASHC5-related intellectual disability, congenital cardiac malformation, and Dandy-Walker malformation

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Ritscher-Schinzel syndrome 1

MIM #220210

Molecular basis of disorder known

Autosomal recessive

Spastic paraplegia 8, autosomal dominant

MIM #603563

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — WASHC5
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Expanding the pre- and postnatal phenotype of WASHC5 and CCDC22 -related Ritscher-Schinzel syndromes.
Neri S et al.·Eur J Med Genet
2022
Clinical and molecular characteristics of 26 fetuses with lethal multiple congenital contractures.
Turgut GT et al.·Clin Genet
2024
[Autosomal dominant spastic paraplegias].
Rudenskaya GE et al.·Zh Nevrol Psikhiatr Im S S Korsakova
2021
A Retrospective Review of 18 Patients With Childhood-Onset Hereditary Spastic Paraplegia, Nine With Novel Variants.
Kilic MA et al.·Pediatr Neurol
2024Review
Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome.
Otsuji S et al.·J Med Genet
2023Functional
Hereditary spastic paraplegia SPG8 mutations impair CAV1-dependent, integrin-mediated cell adhesion.
Lee S et al.·Sci Signal
2020
CCDC22 mutations that impair COMMD binding cause attenuated 3C/Ritscher-Schinzel syndrome.
Singla A et al.·BMC Med Genomics
2025
Brain Damage and Gene Expression Across Hereditary Spastic Paraplegia Subtypes.
Servelhere KR et al.·Mov Disord
2021
Expansion of the CCDC22 associated Ritscher-Schinzel/3C syndrome and review of the literature: Should the minimal diagnostic criteria be revised?
Gjerulfsen CE et al.·Eur J Med Genet
2021Review
Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex.
Kato K et al.·J Med Genet
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools