# NM_001142800.2(EYS):c.962del (p.Pro321fs)

https://sugi.bio/variant/eys-p-pro321fs

## Summary

**EYS p.Pro321fs (c.962del)** is classified **Pathogenic/Likely pathogenic** in EYS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-22). Very rare (popmax 8.48e-05%, nfe); Associated with EYS-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1766681441 · 2 submitters · 1 linked condition · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the EYS gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to EYS-related disorder.

*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 | [EYS](https://sugi.bio/atlas/gene/EYS/) |
| Protein change (HGVS p.) | p.Pro321fs |
| Coding change (HGVS c.) | c.962del |
| MANE Select transcript | [NM_001142800](https://www.ncbi.nlm.nih.gov/nuccore/NM_001142800) |
| dbSNP | [rs1766681441](https://www.ncbi.nlm.nih.gov/snp/rs1766681441/) |
| Variant type | Deletion |
| Location | chr6:65405268-65405268 (GRCh38) |
| ClinVar | [VCV2036122](https://www.ncbi.nlm.nih.gov/clinvar/variation/2036122/) |

**All HGVS expressions:** `NC_000006.11:g.66115163del`, `NC_000006.12:g.65405270del`, `NG_023443.2:g.306958del`, `NM_001142800.2:c.962del`, `NM_001142801.2:c.962del`, `NM_001292009.2:c.962del`, `NM_198283.2:c.962del`

## 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 -0.141, GERP 1.15 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.96, pLI 6.4354e-50. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 43**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 14.45**. 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: **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) · 1/1,179,522 in the highest group · 1/1,613,212 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}

**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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-22.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (2022–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-10-19 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-10-22 |

## Associated conditions {#conditions}

[EYS-related disorder](https://sugi.bio/atlas/disease/eys-related-disorder/).

**Reported phenotype names (ClinVar):** EYS-related disorder, not provided, none provided, EYS-related condition.

## Similar variants {#similar}

Related EYS variant pages (same residue, condition, or type): [EYS p.Ala2957fs](/variant/eys-p-ala2957fs), [EYS p.Asn1773_Val1781delinsLys](/variant/eys-p-asn1773-val1781delinslys), [EYS p.Asn2918fs](/variant/eys-p-asn2918fs), [EYS p.Asn328fs](/variant/eys-p-asn328fs), [EYS p.Cys412fs](/variant/eys-p-cys412fs), [EYS p.Cys78fs](/variant/eys-p-cys78fs), [EYS p.Gln2723fs](/variant/eys-p-gln2723fs), [EYS p.Gln3053fs](/variant/eys-p-gln3053fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 2036122). 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.*