ESRP1

ESRP1 was first reported in relation to autosomal recessive nonsyndromic genetic hearing loss in 2017 (Rohachek et al., PMID: 29107558). 2 variants (missense, frameshift) that have been reported in 2 probands from 1 family in 1 publication (PMIDs: 29107558) are included in this curation. These probands were affected with congenital bilateral severe-to-profound sensorineural hearing loss and vestibular anomalies. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse model, expression-level evidence; PMIDs: 29107558, 19285943). A mouse model shows that homozygous mutants had fluid-filled cysts with no vestibular or cochlear outgrowth; abnormal cochlear structure; and delayed differentiation of hair cells in the cochlear duct. The mouse model was downgraded because hearing thresholds were not measured. There was also evidence of interaction between ESRP1 and other hearing-loss associated genes including POU4F3, FGFR2, EYA4, and COL11A2, but this was not scored due to lack of both specificity and strong evidence of causation (PMID: 29107558). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Hearing Loss GCEP on the meeting date 7/16/2025 (SOP Version 11).

hearing loss, autosomal recessive 109LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0033202

Submitter: Labcorp Genetics (formerly Invitae)

hearing loss, autosomal recessive 109MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0033202

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 109AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 29107558

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ESRP1 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 76

ESRP1-related disorderTotal: 14

not providedTotal: 8

Hearing loss, autosomal recessive 109Total: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017697.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	13 clinvar	2 clinvar	17
missense	1 clinvar	1 clinvar	75 clinvar	3 clinvar	1 clinvar	81
nonsense						0
start loss						0
frameshift	1 clinvar	1 clinvar				2
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	2	2	79	16	3	102

Highest pathogenic variant AF is 0.000006571425

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017697.4	RefSeq	NP_060167.2	15	MANE Select
ENST00000433389.8	Ensembl	ENSP00000405738.2	15	MANE Select
NM_001034915.3	RefSeq	NP_001030087.2	15	Standard
NM_001122825.2	RefSeq	NP_001116297.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

FGFR2 alternative splicing
Signaling by FGFR2
Disease
Signal Transduction
Signaling by FGFR

Biological Process

mRNA processing
RNA splicing
fibroblast growth factor receptor signaling pathway
regulation of inner ear auditory receptor cell fate specification
regulation of RNA splicing

Molecular Function

mRNA binding
protein binding

Cellular Component

nucleus
nucleoplasm
nuclear body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000433389
Coding exons: 15
Length: 66393
Individuals with no LoFs: 124629
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 124639
p: 0.0000401

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.27	245	367	0.667	0.0000184	4424
Missense (PolyPhen)		58	129.53	0.44778		1473
Synonymous	0.0965	140	141	0.990	0.00000758	1351
Loss of Function	5.17	4	38.8	0.103	0.00000232	423

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000066	0.000065	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00017	0.00017	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000037	0.000035	rare
South Asian	0.000077	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: mRNA splicing factor that regulates the formation of epithelial cell-specific isoforms. Specifically regulates the expression of FGFR2-IIIb, an epithelial cell-specific isoform of FGFR2. Also regulates the splicing of CD44, CTNND1, ENAH, 3 transcripts that undergo changes in splicing during the epithelial-to-mesenchymal transition (EMT). Acts by directly binding specific sequences in mRNAs. Binds the GU-rich sequence motifs in the ISE/ISS-3, a cis-element regulatory region present in the mRNA of FGFR2 (PubMed:19285943). Regulates splicing and expression of genes involved in inner ear development, auditory hair cell differentiation, and cell fate specification in the cochlear epithelium (By similarity). {ECO:0000250|UniProtKB:Q3US41, ECO:0000269|PubMed:19285943}.;
Disease: DISEASE: Deafness, autosomal recessive, 109 (DFNB109) [MIM:618013]: A form of non-syndromic, sensorineural deafness characterized by bilateral, congenital, severe to profound hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNB109 affected individuals additionally exhibit vestibular dysplasia, although they do not manifest problems with balance or movement. {ECO:0000269|PubMed:29107558}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.120

Intolerance Scores

LoFtool: 0.594
RVIS EVS: -0.53
RVIS percentile EVS: 20.7

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.215

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium