DPYSL4

Chr 10

dihydropyrimidinase like 4

Also known as: CRMP3, DRP-4, ULIP4

NCBI Gene: 10570 ENSG00000151640 UniProt: O14531

The protein is necessary for signaling by class 3 semaphorins and subsequent cytoskeleton remodeling, playing a role in axon guidance, neuronal growth cone collapse and cell migration. Mutations in DPYSL4 cause autosomal recessive developmental and epileptic encephalopathy with microcephaly, presenting in infancy with seizures, severe developmental delay, and progressive microcephaly. The gene shows moderate constraint against loss-of-function variants, and the condition primarily affects the central nervous system with early onset neurological manifestations.

ResearchSummary from RefSeq, UniProt

Enables filamin binding activity. Predicted to be involved in nervous system development. Predicted to be located in cytoplasm. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.89

Clinical Summary— DPYSL4

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

100 VUS of 112 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.89LOEUF

pLI 0.000

Z-score 2.02

OE 0.59 (0.41–0.89)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.15Z-score

OE missense 0.84 (0.77–0.92)

330 obs / 394.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.59 (0.41–0.89)

0≤0.351.4

Missense OE?0.84 (0.77–0.92)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 17 / 28.7Missense obs/exp: 330 / 394.0Syn Z: -0.71

This gene — mechanism propensity

0.7131th %ile

GOF

0.6834th %ile

LOF

0.3453th %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.

ClinVar Variant Classifications

112 submitted variants in ClinVar

ClinVar

Classification Summary

VUS100

Likely Benign4

100

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	100	0	100
Likely Benign	3	1	4
Benign	0	0	0
Total	103	1	104

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

View in ClinVar →

98 pathogenic / likely-pathogenic (of 106) ClinVar copy-number / structural variants overlap DPYSL4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →