# NM_000275.3(OCA2):c.1555del (p.Val519fs)

https://sugi.bio/variant/oca2-p-val519fs

## Summary

**OCA2 p.Val519fs (c.1555del)** is classified **Pathogenic/Likely pathogenic** in OCA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-02). Very rare (popmax 0.00267%, afr); Associated with OCA2-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs765235945 · 3 submitters · 1 linked condition · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the OCA2 gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to OCA2-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 | [OCA2](https://sugi.bio/atlas/gene/OCA2/) |
| Protein change (HGVS p.) | p.Val519fs |
| Coding change (HGVS c.) | c.1555del |
| MANE Select transcript | [NM_000275](https://www.ncbi.nlm.nih.gov/nuccore/NM_000275) |
| dbSNP | [rs765235945](https://www.ncbi.nlm.nih.gov/snp/rs765235945/) |
| Variant type | Deletion |
| Location | chr15:27966771-27966771 (GRCh38) |
| ClinVar | [VCV1458413](https://www.ncbi.nlm.nih.gov/clinvar/variation/1458413/) |

**All HGVS expressions:** `NC_000015.10:g.27966771del`, `NC_000015.9:g.28211917del`, `NG_009846.1:g.137542del`, `NM_000275.2:c.1555delG`, `NM_000275.3:c.1555del`, `NM_001300984.2:c.1483del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.003, GERP 1.82, phastCons 0.997 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.869, pLI 1.9006e-14. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 15 of 24**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 24.2**. 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 **0.00267%** (afr) · FAF95 0.000443% · FAF99 0.000166% · 2/74,912 in the highest group · 2/1,613,540 alleles overall — very rare (popmax 0.00267%, afr).

*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}

**OCA2** population constraint: LOEUF 0.869, pLI 1.9006e-14, missense-Z 0.96565; 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):

- **oculocutaneous albinism type 2** — Definitive (AR)

## Protein context {#protein}

Residue **519** lies in a UniProt-annotated variant site (in).

AlphaFold model confidence (whole protein): pLDDT 73.79, 27% of residues very-high.

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

*Describes the biological roles of OCA2 (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.*

**How this variant is thought to act:** OCA2's established molecular role includes chloride channel activity.


### Pathways affected {#pathways}

OCA2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Melanin biosynthesis](https://reactome.org/content/detail/R-HSA-5662702) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** chloride channel activity.

**Biological process:** melanin biosynthetic process from tyrosine, lysosomal lumen pH elevation.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-12-02.

**Submitter consensus:** conflicting (2 Pathogenic, 1 Likely pathogenic).

**Submission history:** 3 submissions (2022–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Pathogenic | criteria provided, single submitter | clinical testing | 2023-05-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-02 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-11-17 |

## Associated conditions {#conditions}

[OCA2-related disorder](https://sugi.bio/atlas/disease/oca2-related-disorder/).

**Reported phenotype names (ClinVar):** OCA2-related disorder, not provided, OCA2-related condition, none provided.

## Similar variants {#similar}

Related OCA2 variant pages (same residue, condition, or type): [OCA2 c.647-12_647-1del](/variant/oca2-c-647-minus-12-647-minus-1del), [OCA2 p.Ala55fs](/variant/oca2-p-ala55fs), [OCA2 p.Ala696fs](/variant/oca2-p-ala696fs), [OCA2 p.Asn442del](/variant/oca2-p-asn442del), [OCA2 p.Asn603fs](/variant/oca2-p-asn603fs), [OCA2 p.Ile742fs](/variant/oca2-p-ile742fs), [OCA2 p.Leu207_Leu212del](/variant/oca2-p-leu207-leu212del), [OCA2 p.Leu316_Leu317insTer](/variant/oca2-p-leu316-leu317inster).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1458413). 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.*