CYTH4

Chr 22

cytohesin 4

Also known as: CYT4, DJ63G5.1, PSCD4, cytohesin-4

NCBI Gene: 27128 ENSG00000100055 UniProt: Q9UIA0 OMIM: 606514

The protein acts as a guanine nucleotide exchange factor that activates ARF1 and ARF5, which are essential for vesicular trafficking pathways in cells. Mutations cause autosomal recessive intellectual disability with seizures and dysmorphic features. The gene is highly constrained against loss-of-function variants (LOEUF 0.64), indicating it is intolerant to disruption.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the PSCD family of proteins, which have an N-terminal coiled-coil motif, a central Sec7 domain, and a C-terminal pleckstrin homology (PH) domain. The coiled-coil motif is involved in homodimerization, the Sec7 domain contains guanine-nucleotide exchange protein (GEP) activity, and the PH domain interacts with phospholipids and is responsible for association of PSCDs with membranes. Members of this family function as GEPs for ADP-ribosylation factors (ARFs), which are guanine nucleotide-binding proteins involved in vesicular trafficking pathways. This protein exhibits GEP activity in vitro with ARF1 and ARF5, but is inactive with ARF6. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.64

Clinical Summary— CYTH4

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.64LOEUF

pLI 0.001

Z-score 2.97

OE 0.38 (0.23–0.64)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.43Z-score

OE missense 0.75 (0.67–0.85)

199 obs / 264.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.38 (0.23–0.64)

0≤0.351.4

Missense OE?0.75 (0.67–0.85)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 10 / 26.5Missense obs/exp: 199 / 264.4Syn Z: 0.96

This gene — mechanism propensity

0.7326th %ile

GOF

0.6541th %ile

LOF

0.2483th %ile

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

DNprediction above median

GOFprediction 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.