JOSD1

Chr 22

Josephin domain containing 1

Also known as: dJ508I15.2

NCBI Gene: 9929 ENSG00000100221 UniProt: Q15040 OMIM: 615323

The JOSD1 protein functions as a deubiquitinating enzyme that cleaves ubiquitin chains and regulates endocytosis and membrane dynamics. Mutations cause autosomal recessive neurodevelopmental disorder with early infantile epileptic encephalopathy, developmental delay, and intellectual disability. This gene is not highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable cysteine-type deubiquitinase activity. Predicted to be involved in proteolysis. Predicted to act upstream of or within several processes, including endocytosis; membrane biogenesis; and protein deubiquitination. Located in membrane. [provided by Alliance of Genome Resources, Apr 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.83

Clinical Summary— JOSD1

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Population Constraint (gnomAD)

Low constraint (pLI 0.04) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.83LOEUF

pLI 0.045

Z-score 1.97

OE 0.36 (0.18–0.83)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.81Z-score

OE missense 0.53 (0.43–0.66)

63 obs / 118.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.36 (0.18–0.83)

0≤0.351.4

Missense OE?0.53 (0.43–0.66)

0≤0.61.4

Synonymous OE?1.32

0≤1.21.6

LoF obs/exp: 4 / 11.1Missense obs/exp: 63 / 118.5Syn Z: -1.75

This gene — mechanism propensity

0.6649th %ile

GOF

0.77top 25%

LOF

0.2581th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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