# NM_031475.3(ESPN):c.1345C>G (p.Pro449Ala)

https://sugi.bio/variant/espn-p-pro449ala

## Summary

**ESPN p.Pro449Ala (c.1345C>G)** is classified **Uncertain significance** in ESPN (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-01-01). AlphaMissense: likely benign (0.1114); Absent from gnomAD v4.1; Associated with inherited retinal dystrophy.

**At a glance:** Uncertain significance · review: No assertion criteria · 1 submitter · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## 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 inherited retinal dystrophy.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 40 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018916/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.Pro449Ala |
| Coding change (HGVS c.) | c.1345C>G |
| MANE Select transcript | [NM_031475](https://www.ncbi.nlm.nih.gov/nuccore/NM_031475) |
| Variant type | single nucleotide variant |
| Location | chr1:6445816-6445816 (GRCh38) |
| ClinVar | [VCV3249454](https://www.ncbi.nlm.nih.gov/clinvar/variation/3249454/) |

**All HGVS expressions:** `LRG_1281:g.26029C>G`, `LRG_1281t1:c.1345C>G`, `NC_000001.10:g.6505876C>G`, `NC_000001.11:g.6445816C>G`, `NG_015866.1:g.26029C>G`, `NM_001367473.1:c.1345C>G`, `NM_001367474.1:c.1345C>G`, `NM_031475.3:c.1345C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1114)
- REVEL 0.266 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.425 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 5.589, GERP 1.43, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.9**. 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 0.58** across the covering region of the MANE Select transcript (6,445,787–6,448,933), spanning 3,146 bp. Chi-square p 3.4e-10. 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, Δ0.30 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **449** 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 No assertion criteria *(no assertion criteria provided)*, last evaluated 2022-01-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Uncertain significance | no assertion criteria provided | clinical testing | 2022-01-01 |

## Associated conditions {#conditions}

[inherited retinal dystrophy](https://sugi.bio/atlas/disease/inherited-retinal-dystrophy/).

**Reported phenotype names (ClinVar):** Retinal dystrophy, Inherited retinal dystrophy.

## Similar variants {#similar}

Related ESPN variant pages (same residue, condition, or type): [ESPN p.Pro449=](/variant/espn-p-pro449), [ESPN p.Arg113His](/variant/espn-p-arg113his), [ESPN p.Arg335Cys](/variant/espn-p-arg335cys), [ESPN p.Ser312Leu](/variant/espn-p-ser312leu), [ESPN p.Ser342Phe](/variant/espn-p-ser342phe), [ESPN p.Val165Met](/variant/espn-p-val165met), [ESPN c.858+11G>T](/variant/espn-c-858-plus-11g-t), [ESPN p.Arg113Cys](/variant/espn-p-arg113cys).

### 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 3249454). 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.*