WDR81

Chr 17AR

WD repeat domain 81

Also known as: CAMRQ2, CHMRQ, HYC3, PPP1R166, SORF-2

NCBI Gene: 124997 ENSG00000167716 UniProt: Q562E7 OMIM: 614218

This protein functions as a negative regulator of PI3 kinase activity on endosomal membranes and is required for endosome fusion, recycling, and early-to-late endosome transport, as well as aggrephagy of ubiquitinated protein aggregates. Biallelic mutations cause autosomal recessive cerebellar ataxia with impaired intellectual development and dysquilibrium syndrome (CAMRQ2) and congenital hydrocephalus with brain anomalies through loss-of-function mechanisms that disrupt endolysosomal trafficking. The gene shows moderate constraint against loss-of-function variants, consistent with recessive inheritance requiring biallelic mutations for disease manifestation.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a multi-domain transmembrane protein which is predominantly expressed in the brain and is thought to play a role in endolysosomal trafficking. Mutations in this gene are associated with an autosomal recessive form of a syndrome exhibiting cerebellar ataxia, cognitive disability, and disequilibrium (CAMRQ2). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

OMIM ResearchGenerating clinical summary…

ARLOEUF 0.532 OMIM phenotypes

Clinical Summary— WDR81

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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

37 unique Pathogenic / Likely Pathogenic· 404 VUS of 652 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.53LOEUF

pLI 0.000

Z-score 4.57

OE 0.38 (0.27–0.53)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.11Z-score

OE missense 0.83 (0.79–0.87)

1000 obs / 1206.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.38 (0.27–0.53)

0≤0.351.4

Missense OE?0.83 (0.79–0.87)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 24 / 63.2Missense obs/exp: 1000 / 1206.3Syn Z: 1.60

ClinVar Variant Classifications

652 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic28

VUS404

Likely Benign147

Benign34

Conflicting15

Pathogenic

Likely Pathogenic

404

VUS

147

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	9	0	0	0	9
Likely Pathogenic	22	5	1	0	28
VUS	2	397	2	3	404
Likely Benign	0	25	7	115	147
Benign	0	4	4	26	34
Conflicting	—				15
Total	33	431	14	144	637

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

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78 pathogenic / likely-pathogenic (of 93) ClinVar copy-number / structural variants overlap WDR81 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →