# NM_001142800.2(EYS):c.1512T>A (p.Ala504=)

https://sugi.bio/variant/eys-p-ala504

## Summary

**EYS p.Ala504= (c.1512T>A)** is classified **Conflicting classifications of pathogenicity** in EYS (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-28). Ultra-rare (popmax 0.0642%, afr); Associated with retinitis pigmentosa 25.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs142178909 · 3 submitters · 1 linked condition · ultra-rare (popmax 0.0642%, afr)

## For patients & families {#patients}

This is a change in the EYS gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to retinitis pigmentosa 25.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, Mitochondrial inheritance |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |
| Diagnostic panels | EYS is a diagnostic-grade gene on 1 Genomics England panel |

**Commonly reported features of Retinitis pigmentosa** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Conductive hearing impairment — Very frequent (99-80%)
- Sensorineural hearing impairment — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Abnormal electroretinogram — Very frequent (99-80%)
- Retinal degeneration — Very frequent (99-80%)
- Photophobia — Very frequent (99-80%)
- Blindness — Very frequent (99-80%)
- Nystagmus — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010384/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EYS](https://sugi.bio/atlas/gene/EYS/) |
| Protein change (HGVS p.) | p.Ala504= |
| Coding change (HGVS c.) | c.1512T>A |
| MANE Select transcript | [NM_001142800](https://www.ncbi.nlm.nih.gov/nuccore/NM_001142800) |
| dbSNP | [rs142178909](https://www.ncbi.nlm.nih.gov/snp/rs142178909/) |
| Variant type | single nucleotide variant |
| Location | chr6:65344125-65344125 (GRCh38) |
| ClinVar | [VCV799476](https://www.ncbi.nlm.nih.gov/clinvar/variation/799476/) |

**All HGVS expressions:** `NC_000006.11:g.66054018A>T`, `NC_000006.12:g.65344125A>T`, `NG_023443.2:g.368101T>A`, `NM_001142800.2:c.1512T>A`, `NM_001142801.2:c.1512T>A`, `NM_001292009.2:c.1512T>A`, `NM_198283.2:c.1512T>A`

## 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 gain** (Δ 0.62) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.409, GERP -0.4 — weakly conserved position
- CADD: **PHRED 16.59**. 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 **0.00**, donor loss **0.00**, acceptor gain **0.62**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.62**, donor gain **0.00**.
- Pangolin: Δ**0.23** (gain), gain 0.23 / loss 0.00. 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 **0.0642%** (afr) · FAF95 0.0496% · FAF99 0.0445% · 48/74,810 in the highest group · 67/1,610,708 alleles overall — ultra-rare (popmax 0.0642%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0642% | 1,559 |
| Admixed American | 0.0201% | 4,974 |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,902 |

*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}

**EYS** population constraint: LOEUF 0.96, pLI 6.4354e-50, missense-Z -0.45186. *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):

- **EYS-related retinopathy** — Definitive (AR)

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-28.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Likely benign).

**Submission history:** 3 submissions (2019–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2019-11-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-11 |

## Associated conditions {#conditions}

[retinitis pigmentosa 25](https://sugi.bio/atlas/disease/retinitis-pigmentosa-25/).

**Reported phenotype names (ClinVar):** not provided, Retinitis pigmentosa 25, none provided.

## Similar variants {#similar}

Related EYS variant pages (same residue, condition, or type): [EYS c.1056+1G>A](/variant/eys-c-1056-plus-1g-a), [EYS c.1056+3A>C](/variant/eys-c-1056-plus-3a-c), [EYS c.1057-1G>A](/variant/eys-c-1057-minus-1g-a), [EYS c.1184+1G>A](/variant/eys-c-1184-plus-1g-a), [EYS c.1184+1G>T](/variant/eys-c-1184-plus-1g-t), [EYS c.1185-1G>A](/variant/eys-c-1185-minus-1g-a), [EYS c.1299+2T>A](/variant/eys-c-1299-plus-2t-a), [EYS c.1599+1G>T](/variant/eys-c-1599-plus-1g-t).

### 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 799476). 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.*