# NM_031475.3(ESPN):c.1015C>T (p.Arg339Trp)

https://sugi.bio/variant/espn-p-arg339trp

## Summary

**ESPN p.Arg339Trp (c.1015C>T)** is classified **Uncertain significance** in ESPN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-01). AlphaMissense: likely benign (0.2088); Ultra-rare (popmax 0.0446%, eas).

**At a glance:** Uncertain significance · review: Multiple submitters · 2 submitters · AlphaMissense likely benign · ultra-rare (popmax 0.0446%, eas)

## For patients & families {#patients}

This is a change in the ESPN gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters.

*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:** [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.Arg339Trp |
| Coding change (HGVS c.) | c.1015C>T |
| MANE Select transcript | [NM_031475](https://www.ncbi.nlm.nih.gov/nuccore/NM_031475) |
| Variant type | single nucleotide variant |
| Location | chr1:6444505-6444505 (GRCh38) |
| ClinVar | [VCV4281097](https://www.ncbi.nlm.nih.gov/clinvar/variation/4281097/) |

**All HGVS expressions:** `LRG_1281:g.24718C>T`, `LRG_1281t1:c.1015C>T`, `NC_000001.10:g.6504565C>T`, `NC_000001.11:g.6444505C>T`, `NG_015866.1:g.24718C>T`, `NM_001367473.1:c.1015C>T`, `NM_001367474.1:c.1015C>T`, `NM_031475.3:c.1015C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2088)
- REVEL 0.666 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -6.788 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 2.289, GERP 1.36, phastCons 0.984 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.8**. 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.*
- Regional missense constraint: **o/e 0.88** across the covering region of the MANE Select transcript (6,424,956–6,445,786), spanning 20,830 bp. Chi-square p 0.002. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.27 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 **0.0446%** (eas) · FAF95 0.0295% · FAF99 0.0246% · 20/44,890 in the highest group · 41/1,614,066 alleles overall — ultra-rare (popmax 0.0446%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 0.987% | 101 |
| East Asian (grpmax) | 0.0446% | 2,244 |
| South Asian | 0.0022% | 45,544 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,482 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,038 |
| European (non-Finnish) | 0.000678% | 147,504 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **339** 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-01.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-01 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-10-11 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ESPN variant pages (same residue, condition, or type): [ESPN p.Arg339Gln](/variant/espn-p-arg339gln), [ESPN c.1464+1G>A](/variant/espn-c-1464-plus-1g-a), [ESPN p.Ala139Thr](/variant/espn-p-ala139thr), [ESPN p.Ala23Thr](/variant/espn-p-ala23thr), [ESPN p.Ala484Thr](/variant/espn-p-ala484thr), [ESPN p.Ala591Val](/variant/espn-p-ala591val), [ESPN p.Ala610Pro](/variant/espn-p-ala610pro), [ESPN p.Ala624Thr](/variant/espn-p-ala624thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 4281097). 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.*