# NM_031475.3(ESPN):c.1386A>G (p.Val462=)

https://sugi.bio/variant/espn-p-val462

## Summary

**ESPN p.Val462= (c.1386A>G)** is classified **Benign/Likely benign** in ESPN (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-17). Rare (popmax 0.793%, afr); Associated with autosomal recessive nonsyndromic hearing loss 36.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs150033799 · 6 submitters · 2 linked conditions · rare (popmax 0.793%, afr)

## For patients & families {#patients}

This is a change in the ESPN gene that is classified as benign/likely benign — not considered disease-causing, submitted by 6 submitters, and is linked to autosomal recessive nonsyndromic hearing loss 36.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022611/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ESPN](https://sugi.bio/atlas/gene/ESPN/) |
| Protein change (HGVS p.) | p.Val462= |
| Coding change (HGVS c.) | c.1386A>G |
| MANE Select transcript | [NM_031475](https://www.ncbi.nlm.nih.gov/nuccore/NM_031475) |
| dbSNP | [rs150033799](https://www.ncbi.nlm.nih.gov/snp/rs150033799/) |
| Variant type | single nucleotide variant |
| Location | chr1:6445857-6445857 (GRCh38) |
| ClinVar | [VCV1012722](https://www.ncbi.nlm.nih.gov/clinvar/variation/1012722/) |

**All HGVS expressions:** `LRG_1281:g.26070A>G`, `LRG_1281t1:c.1386A>G`, `NC_000001.10:g.6505917A>G`, `NC_000001.11:g.6445857A>G`, `NG_015866.1:g.26070A>G`, `NM_001367473.1:c.1386A>G`, `NM_001367474.1:c.1386A>G`, `NM_031475.3:c.1386A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -0.101, GERP -2.71 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.636**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.47 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.793%** (afr) · FAF95 0.739% · FAF99 0.718% · 579/73,024 in the highest group · 2,683/1,606,278 alleles overall — rare (popmax 0.793%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.793% | 126 |
| Middle Eastern | 0.481% | 208 |
| Remaining individuals (not grpmax-eligible) | 0.229% | 436 |
| Admixed American | 0.172% | 582 |
| European (non-Finnish) | 0.146% | 683 |
| East Asian | 0.0986% | 1,014 |
| South Asian | 0.0528% | 1,894 |
| Finnish (not grpmax-eligible) | 0.0161% | 6,211 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0135% | 7,386 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ESPN** population constraint: LOEUF 1.307, pLI 7.2662e-24, missense-Z -1.0887. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **nonsyndromic genetic hearing loss** — Definitive (AR)
- **nonsyndromic genetic hearing loss** — Limited (AD)

## Protein context {#protein}

Residue **462** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 68.76, 38% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of ESPN (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

ESPN participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Sensory processing of sound by inner hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662360) | electronic |
| [Sensory processing of sound by outer hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662361) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** microvillar actin bundle assembly.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-17.

**Submitter consensus:** conflicting (4 Likely benign, 2 Benign).

**Submission history:** 6 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-10-04 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-09-08 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely benign | criteria provided, single submitter | clinical testing | 2023-11-09 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-17 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2020-10-01 |

## Associated conditions {#conditions}

[autosomal recessive nonsyndromic hearing loss 36](https://sugi.bio/atlas/disease/autosomal-recessive-nonsyndromic-hearing-loss-36/), [Usher syndrome, type 1M](https://sugi.bio/atlas/disease/usher-syndrome-type-1m/).

**Reported phenotype names (ClinVar):** Autosomal recessive nonsyndromic hearing loss 36, not provided, Usher syndrome, type 1M, DEAFNESS, AUTOSOMAL RECESSIVE 36, WITH VESTIBULAR INVOLVEMENT, Deafness, autosomal recessive 36, none provided.

## Similar variants {#similar}

Related ESPN variant pages (same residue, condition, or type): [ESPN c.1464+1G>A](/variant/espn-c-1464-plus-1g-a), [ESPN p.Ala624Thr](/variant/espn-p-ala624thr), [ESPN p.Arg755Cys](/variant/espn-p-arg755cys), [ESPN p.Asp744Asn](/variant/espn-p-asp744asn), [ESPN p.Gly747Ser](/variant/espn-p-gly747ser), [ESPN p.Lys476Gln](/variant/espn-p-lys476gln), [ESPN p.Ser312Leu](/variant/espn-p-ser312leu), [ESPN p.Ser342Phe](/variant/espn-p-ser342phe).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1012722). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*