# NM_031475.3(ESPN):c.702C>G (p.Ser234=)

https://sugi.bio/variant/espn-p-ser234

## Summary

**ESPN p.Ser234= (c.702C>G)** is classified **Benign/Likely benign** in ESPN (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-08-12). Low-frequency (popmax 1.32%, mid).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs367944375 · 6 submitters · low-frequency (popmax 1.32%, mid)

## 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.

*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.Ser234= |
| Coding change (HGVS c.) | c.702C>G |
| MANE Select transcript | [NM_031475](https://www.ncbi.nlm.nih.gov/nuccore/NM_031475) |
| dbSNP | [rs367944375](https://www.ncbi.nlm.nih.gov/snp/rs367944375/) |
| Variant type | single nucleotide variant |
| Location | chr1:6440652-6440652 (GRCh38) |
| ClinVar | [VCV508130](https://www.ncbi.nlm.nih.gov/clinvar/variation/508130/) |

**All HGVS expressions:** `LRG_1281:g.20865C>G`, `LRG_1281t1:c.702C>G`, `NC_000001.10:g.6500712C>G`, `NC_000001.11:g.6440652C>G`, `NG_015866.1:g.20865C>G`, `NM_001367473.1:c.702C>G`, `NM_001367474.1:c.702C>G`, `NM_031475.3:c.702C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.23) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -1.748, GERP -3.31 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 9.982**. 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 deltas (raw): acceptor loss **0.23**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 7 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **1.32%** (mid) · FAF95 1.03% · FAF99 0.924% · 50/3,792 in the highest group · 11,188/1,363,488 alleles overall — low-frequency (popmax 1.32%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 1.55% | 65 |
| Middle Eastern (grpmax) | 1.32% | 76 |
| European (non-Finnish) | 0.904% | 111 |
| Remaining individuals (not grpmax-eligible) | 0.867% | 115 |
| African / African-American | 0.516% | 194 |
| Admixed American | 0.504% | 199 |
| South Asian | 0.457% | 219 |
| East Asian | 0.372% | 269 |
| Finnish (not grpmax-eligible) | 0.188% | 533 |

Ashkenazi Jewish 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}


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 2025-08-12.

**Submitter consensus:** conflicting (3 Benign, 3 Likely benign).

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2018-11-16 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-06-03 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2023-11-11 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-08-12 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |

**Reported phenotype names (ClinVar):** not provided, not specified, AllHighlyPenetrant, 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.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), [ESPN p.Ala729Glu](/variant/espn-p-ala729glu).

### 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 508130). 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.*