# NM_004447.6(EPS8):c.1102G>A (p.Val368Met)

https://sugi.bio/variant/eps8-p-val368met

## Summary

**EPS8 p.Val368Met (c.1102G>A)** is classified **Uncertain significance** in EPS8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-12-29). AlphaMissense: ambiguous (0.3533); Very rare (popmax 0.00802%, afr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs763005561 · 2 submitters · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.00802%, afr)

## For patients & families {#patients}

This is a change in the EPS8 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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.Val368Met |
| Coding change (HGVS c.) | c.1102G>A |
| MANE Select transcript | [NM_004447](https://www.ncbi.nlm.nih.gov/nuccore/NM_004447) |
| dbSNP | [rs763005561](https://www.ncbi.nlm.nih.gov/snp/rs763005561/) |
| Variant type | single nucleotide variant |
| Location | chr12:15654293-15654293 (GRCh38) |
| ClinVar | [VCV2277571](https://www.ncbi.nlm.nih.gov/clinvar/variation/2277571/) |

**All HGVS expressions:** `NC_000012.11:g.15807227C>T`, `NC_000012.12:g.15654293C>T`, `NG_041808.1:g.140284G>A`, `NG_041808.2:g.140095G>A`, `NM_001413831.1:c.1102G>A`, `NM_001413832.1:c.1102G>A`, `NM_001413833.1:c.1102G>A`, `NM_001413834.1:c.1102G>A`, `NM_001413835.1:c.862G>A`, `NM_001413836.1:c.862G>A`, `NM_001413837.1:c.685G>A`, `NM_001413838.1:c.322G>A`, `NM_001413839.1:c.1102G>A`, `NM_004447.6:c.1102G>A`, `NR_182221.1:n.1214G>A`, `NR_182222.1:n.1435G>A`, `NR_182223.1:n.1351G>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; SaProt calls this damaging; REVEL does not; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.3533) — no call either way
- REVEL 0.101 (moderately benign-leaning)
- SaProt LLR -10.036 (damaging)
- → **In-silico consensus:** SaProt calls this damaging; REVEL does not; AlphaMissense makes no call
- SpliceAI predicts **acceptor loss** (Δ 0.24) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.834, GERP 2.18, phastCons 1 — highly conserved
- CADD: **PHRED 23.6**. 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 0.96** across the covering region of the MANE Select transcript (15,621,320–15,682,951), spanning 61,631 bp. Chi-square p 0.26. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.24**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.24**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00802%** (afr) · FAF95 0.00347% · FAF99 0.00229% · 6/74,836 in the highest group · 10/1,612,140 alleles overall — very rare (popmax 0.00802%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00802% | 12,473 |
| East Asian | 0.00223% | 44,882 |
| Admixed American | 0.00168% | 59,634 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,442 |
| European (non-Finnish) | 8.48e-05% | 1,179,359 |

*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 30, triplosensitivity 0 (0–3 scale). *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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-12-29.

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

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-02-17 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-12-29 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related EPS8 variant pages (same residue, condition, or type): [EPS8 p.Val368Leu](/variant/eps8-p-val368leu), [EPS8 p.Ala150Val](/variant/eps8-p-ala150val), [EPS8 p.Ala416Asp](/variant/eps8-p-ala416asp), [EPS8 p.Arg195Trp](/variant/eps8-p-arg195trp), [EPS8 p.Arg403Trp](/variant/eps8-p-arg403trp), [EPS8 p.Arg432Gln](/variant/eps8-p-arg432gln), [EPS8 p.Arg434Cys](/variant/eps8-p-arg434cys), [EPS8 p.Arg597Cys](/variant/eps8-p-arg597cys).

### 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 2277571). 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.*