EPPK1

Chr 8AD

epiplakin 1

Also known as: EPIPL, EPIPL1

NCBI Gene: 83481 ENSG00000261150 UniProt: P58107 OMIM: 607553

Epiplakin is a cytoskeletal linker protein that connects to intermediate filaments and controls their reorganization in response to cellular stress, particularly in keratinocytes and other epithelial cells. Mutations cause palmoplantar keratoderma, epidermolytic, type 1, an autosomal dominant skin disorder characterized by thickening of the palms and soles with epidermolysis. The gene shows very low constraint against loss-of-function variants, suggesting tolerance to such mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to the plakin family of proteins, which play a role in the organization of cytoskeletal architecture. This family member is composed of several highly homologous plakin repeats. It may function to maintain the integrity of keratin intermediate filament networks in epithelial cells. Studies of the orthologous mouse protein suggest that it accelerates keratinocyte migration during wound healing. [provided by RefSeq, Oct 2013]

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 1.201 OMIM phenotype

Clinical Summary— EPPK1

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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

354 VUS of 594 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.20LOEUF

pLI 0.000

Z-score 0.27

OE 0.96 (0.78–1.20)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-3.04Z-score

OE missense 1.23 (1.18–1.27)

1768 obs / 1443.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.96 (0.78–1.20)

0≤0.351.4

Missense OE?1.23 (1.18–1.27)

0≤0.61.4

Synonymous OE?1.29

0≤1.21.6

LoF obs/exp: 58 / 60.3Missense obs/exp: 1768 / 1443.0Syn Z: -6.01

This gene — mechanism propensity

0.4884th %ile

GOF

0.82top 10%

LOF

0.3260th %ile

The highest-scoring mechanism for this gene is gain-of-function.

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

594 submitted variants in ClinVar

ClinVar

Classification Summary

VUS354

Likely Benign178

Benign62

354

VUS

178

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	4	350	0	0	354
Likely Benign	2	63	1	112	178
Benign	3	37	1	21	62
Total	9	450	2	133	594

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

View in ClinVar →

62 pathogenic / likely-pathogenic (of 67) ClinVar copy-number / structural variants overlap EPPK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →