# NM_031475.3(ESPN):c.1287del (p.Pro431fs)

https://sugi.bio/variant/espn-p-pro431fs

## Summary

**ESPN p.Pro431fs (c.1287del)** is classified **Uncertain significance** in ESPN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-22). Ultra-rare (popmax 0.0232%, mid); Associated with Usher syndrome, type 1M.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 2 linked conditions · ultra-rare (popmax 0.0232%, mid)

## 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 1 submitter, and is linked to Usher syndrome, type 1M.

*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/0016370/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.Pro431fs |
| Coding change (HGVS c.) | c.1287del |
| MANE Select transcript | [NM_031475](https://www.ncbi.nlm.nih.gov/nuccore/NM_031475) |
| Variant type | Deletion |
| Location | chr1:6445758-6445758 (GRCh38) |
| ClinVar | [VCV3779629](https://www.ncbi.nlm.nih.gov/clinvar/variation/3779629/) |

**All HGVS expressions:** `LRG_1281:g.25971del`, `LRG_1281t1:c.1287del`, `NC_000001.10:g.6505818del`, `NC_000001.11:g.6445758del`, `NG_015866.1:g.25971del`, `NM_001367473.1:c.1287del`, `NM_001367474.1:c.1287del`, `NM_031475.3:c.1287del`

## 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 1.01, GERP -1.5, phastCons 0.001 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.307, pLI 7.2662e-24. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 13**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 20.2**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Repeat context: **segmental_duplication** (chr1:16689054, chr1_KI270714v1_random:14895). Short reads may not map uniquely here, so both the call and its population frequency are less reliable. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- Population frequency (gnomAD v4.1): grpmax **0.0232%** (mid) · FAF95 0.00323% · FAF99 0.00249% · 1/4,318 in the highest group · 54/1,375,478 alleles overall — ultra-rare (popmax 0.0232%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0232% | 4,318 |
| East Asian | 0.00957% | 10,454 |
| Admixed American | 0.00547% | 18,277 |
| European (non-Finnish) | 0.00375% | 26,635 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00351% | 28,520 |
| Finnish (not grpmax-eligible) | 0.00338% | 29,597 |
| African / African-American | 0.00139% | 71,732 |

*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 **431** 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 Single submitter *(criteria provided, single submitter)*, last evaluated 2023-08-22.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | criteria provided, single submitter | research | 2023-08-22 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Usher syndrome, type 1M, Autosomal recessive nonsyndromic hearing loss 36, DEAFNESS, AUTOSOMAL RECESSIVE 36, WITH VESTIBULAR INVOLVEMENT, Deafness, autosomal recessive 36.

## Similar variants {#similar}

Related ESPN variant pages (same residue, condition, or type): [ESPN p.Pro431Ala](/variant/espn-p-pro431ala), [ESPN p.Pro431=](/variant/espn-p-pro431), [ESPN p.Arg550fs](/variant/espn-p-arg550fs), [ESPN p.Arg790_Arg795del](/variant/espn-p-arg790-arg795del), [ESPN p.Lys666fs](/variant/espn-p-lys666fs), [ESPN p.Ser694fs](/variant/espn-p-ser694fs), [ESPN p.Gly831_Tyr832insTer](/variant/espn-p-gly831-tyr832inster), [ESPN p.Lys663fs](/variant/espn-p-lys663fs).

### 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 3779629). 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.*