ESRP1

Chr 8AR

epithelial splicing regulatory protein 1

Also known as: DFNB109, RBM35A, RMB35A

NCBI Gene: 54845 ENSG00000104413 UniProt: Q6NXG1 OMIM: 612959

ESRP1 encodes an mRNA splicing factor that regulates the formation of epithelial cell-specific isoforms and controls splicing of genes involved in inner ear development and auditory hair cell differentiation. Mutations cause autosomal recessive deafness (DFNB109). The gene is highly constrained against loss-of-function variants, suggesting that complete loss of function is likely pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

ESPR1 is an epithelial cell-type-specific splicing regulator (Warzecha et al., 2009 [PubMed 19285943]).[supplied by OMIM, Aug 2009]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.241 OMIM phenotype

Clinical Summary— ESRP1

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ARLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 68 VUS of 116 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.24LOEUF

pLI 0.999

Z-score 5.17

OE 0.10 (0.05–0.24)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.27Z-score

OE missense 0.67 (0.60–0.74)

245 obs / 367.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.10 (0.05–0.24)

0≤0.351.4

Missense OE?0.67 (0.60–0.74)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 4 / 38.8Missense obs/exp: 245 / 367.2Syn Z: 0.10

This gene — mechanism propensity

0.3892th %ile

GOF

0.4480th %ile

LOF

0.68top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.24

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

116 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic1

VUS68

Likely Benign16

Benign10

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	1	0	0	2
Likely Pathogenic	1	0	0	0	1
VUS	0	68	0	0	68
Likely Benign	0	3	2	11	16
Benign	0	1	4	5	10
Total	2	73	6	16	97

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

View in ClinVar →

38 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap ESRP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →