EPS15

Chr 1

epidermal growth factor receptor pathway substrate 15

Also known as: AF-1P, AF1P, MLLT5

NCBI Gene: 2060 ENSG00000085832 UniProt: P42566

This protein functions in receptor-mediated endocytosis, particularly of growth factor receptors like EGFR, and plays a role in clathrin-coated pit assembly and maturation. Mutations cause autosomal recessive developmental and epileptic encephalopathy with early infantile onset, characterized by severe intellectual disability, seizures, and microcephaly. The gene is highly constrained against loss-of-function variants in the general population.

ResearchSummary from RefSeq, UniProt

This gene encodes a protein that is part of the EGFR pathway. The protein is present at clatherin-coated pits and is involved in receptor-mediated endocytosis of EGF. Notably, this gene is rearranged with the HRX/ALL/MLL gene in acute myelogeneous leukemias. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2009]

ResearchGenerating clinical summary…

LOEUF 0.46

Clinical Summary— EPS15

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.

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ClinVar Variants

107 VUS of 142 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

Moderate LoF intolerance

LoF Constraint?

0.46LOEUF

pLI 0.003

Z-score 4.56

OE 0.29 (0.19–0.46)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.78Z-score

OE missense 0.90 (0.82–0.97)

402 obs / 448.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.29 (0.19–0.46)

0≤0.351.4

Missense OE?0.90 (0.82–0.97)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 14 / 48.2Missense obs/exp: 402 / 448.6Syn Z: 0.37

ClinVar Variant Classifications

142 submitted variants in ClinVar

ClinVar

Classification Summary

VUS107

Likely Benign2

107

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	107	107
Likely Benign	2	2
Benign	0	0
Total	109	109

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap EPS15 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →