# NM_004447.6(EPS8):c.2312C>T (p.Ala771Val)

https://sugi.bio/variant/eps8-p-ala771val

## Summary

**EPS8 p.Ala771Val (c.2312C>T)** is classified **Uncertain significance** in EPS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-07). AlphaMissense: likely benign (0.1312); Very rare (popmax 0.0011%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.0011%, sas)

## 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 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.Ala771Val |
| Coding change (HGVS c.) | c.2312C>T |
| MANE Select transcript | [NM_004447](https://www.ncbi.nlm.nih.gov/nuccore/NM_004447) |
| Variant type | single nucleotide variant |
| Location | chr12:15623201-15623201 (GRCh38) |
| ClinVar | [VCV4915779](https://www.ncbi.nlm.nih.gov/clinvar/variation/4915779/) |

**All HGVS expressions:** `NC_000012.11:g.15776135G>A`, `NC_000012.12:g.15623201G>A`, `NG_041808.1:g.171376C>T`, `NG_041808.2:g.171187C>T`, `NM_001413831.1:c.2348C>T`, `NM_001413832.1:c.2312C>T`, `NM_001413833.1:c.2312C>T`, `NM_001413834.1:c.2312C>T`, `NM_001413835.1:c.2072C>T`, `NM_001413836.1:c.2072C>T`, `NM_001413837.1:c.1895C>T`, `NM_001413838.1:c.1532C>T`, `NM_004447.6:c.2312C>T`, `NR_182221.1:n.2424C>T`, `NR_182222.1:n.2645C>T`, `NR_182223.1:n.2556C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1312)
- REVEL 0.171 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.064 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.54) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 9.944, GERP 2.72, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 27.9**. 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 0.96** 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 **0.03**, donor loss **0.04**, acceptor gain **0.00**, donor gain **0.54**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.54**.
- Pangolin: Δ**0.29** (gain), gain 0.29 / loss 0.08. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · FAF95 0.000359% · FAF99 0.00026% · 1/90,948 in the highest group · 11/1,612,766 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,442 |
| South Asian (grpmax) | 0.0011% | 90,948 |
| European (non-Finnish) | 0.000763% | 131,058 |

Remaining individuals 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}

**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}

Residue **771** lies in the 'helix bundle 4' region; an α-helix; the 'effector region' region.

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 Single submitter *(criteria provided, single submitter)*, last evaluated 2021-09-07.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-09-07 |

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

## Similar variants {#similar}

Related EPS8 variant pages (same residue, condition, or type): [EPS8 p.Ala771=](/variant/eps8-p-ala771), [EPS8 c.205-8A>G](/variant/eps8-c-205-minus-8a-g), [EPS8 p.Ala150Val](/variant/eps8-p-ala150val), [EPS8 p.Ala219Val](/variant/eps8-p-ala219val), [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).

### 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 4915779). 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.*