# NM_004447.6(EPS8):c.1802_1817del (p.Pro601fs)

https://sugi.bio/variant/eps8-p-pro601fs

## Summary

**EPS8 p.Pro601fs (c.1802_1817del)** is classified **Pathogenic** in EPS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-06). Very rare (popmax 8.48e-05%, nfe).

**At a glance:** Pathogenic · review: Single submitter · rsID rs1565473322 · 1 submitter · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the EPS8 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*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 | [EPS8](https://sugi.bio/atlas/gene/EPS8/) |
| Protein change (HGVS p.) | p.Pro601fs |
| Coding change (HGVS c.) | c.1802_1817del |
| MANE Select transcript | [NM_004447](https://www.ncbi.nlm.nih.gov/nuccore/NM_004447) |
| dbSNP | [rs1565473322](https://www.ncbi.nlm.nih.gov/snp/rs1565473322/) |
| Variant type | Deletion |
| Location | chr12:15640707-15640722 (GRCh38) |
| ClinVar | [VCV2127162](https://www.ncbi.nlm.nih.gov/clinvar/variation/2127162/) |

**All HGVS expressions:** `NC_000012.11:g.15793641_15793656del`, `NC_000012.12:g.15640707_15640722del`, `NG_041808.1:g.153855_153870del`, `NG_041808.2:g.153666_153681del`, `NM_001413831.1:c.1802_1817del16`, `NM_001413832.1:c.1802_1817del16`, `NM_001413833.1:c.1802_1817del16`, `NM_001413834.1:c.1802_1817del16`, `NM_001413835.1:c.1562_1577del16`, `NM_001413836.1:c.1562_1577del16`, `NM_001413837.1:c.1385_1400del16`, `NM_001413838.1:c.1022_1037del16`, `NM_004447.6:c.1802_1817del`, `NR_182221.1:n.1914_1929del16`, `NR_182222.1:n.2135_2150del16`, `NR_182223.1:n.2046_2061del16`

## 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 0.247, GERP -1.47, phastCons 0.996 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.443, pLI 0.99945), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 17 of 21**, so the transcript is predicted to undergo NMD.
- 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.
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,592 in the highest group · 1/1,613,638 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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}

**EPS8** population constraint: LOEUF 0.443, pLI 0.99945, missense-Z 0.70282; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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):

- **autosomal recessive nonsyndromic hearing loss 102** — Moderate (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 70.77, 32% of residues very-high.

**2 experimental structure(s)** (PDB): [2E8M](https://www.rcsb.org/structure/2E8M), [7TZK](https://www.rcsb.org/structure/7TZK).

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

*Describes the biological roles of EPS8 (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}

EPS8 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 |

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-08-06.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-08-06 |

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

## Similar variants {#similar}

Related EPS8 variant pages (same residue, condition, or type): [EPS8 p.Pro601Thr](/variant/eps8-p-pro601thr), [EPS8 c.1434+14del](/variant/eps8-c-1434-plus-14del), [EPS8 c.2226-3del](/variant/eps8-c-2226-minus-3del), [EPS8 p.Gln137fs](/variant/eps8-p-gln137fs), [EPS8 p.Glu155fs](/variant/eps8-p-glu155fs), [EPS8 c.2225+4_2225+5del](/variant/eps8-c-2225-plus-4-2225-plus-5del), [EPS8 c.1250+119del](/variant/eps8-c-1250-plus-119del), [EPS8 c.1250+19_1250+28del](/variant/eps8-c-1250-plus-19-1250-plus-28del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2127162). 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.*