# NM_000322.5(PRPH2):c.991del (p.Gln331fs)

https://sugi.bio/variant/prph2-p-gln331fs

## Summary

**PRPH2 p.Gln331fs (c.991del)** is classified **Pathogenic** in PRPH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-28). No gnomAD frequency available for this variant; Associated with PRPH2-related disorder.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2152003795 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PRPH2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to PRPH2-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 | [PRPH2](https://sugi.bio/atlas/gene/PRPH2/) |
| Protein change (HGVS p.) | p.Gln331fs |
| Coding change (HGVS c.) | c.991del |
| MANE Select transcript | [NM_000322](https://www.ncbi.nlm.nih.gov/nuccore/NM_000322) |
| dbSNP | [rs2152003795](https://www.ncbi.nlm.nih.gov/snp/rs2152003795/) |
| Variant type | Deletion |
| Location | chr6:42698345-42698345 (GRCh38) |
| ClinVar | [VCV1053626](https://www.ncbi.nlm.nih.gov/clinvar/variation/1053626/) |

**All HGVS expressions:** `NC_000006.11:g.42666084del`, `NC_000006.12:g.42698346del`, `NG_009176.2:g.29276del`, `NM_000322.5:c.991del`

## 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 7.819, GERP 1.5, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.773, pLI 0.0060809. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (3 of 3)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- 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: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**PRPH2** population constraint: LOEUF 0.773, pLI 0.0060809, missense-Z 0.58257. *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):

- **PRPH2-related retinopathy** — Definitive (SD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 87.56, 67% of residues very-high.

**1 experimental structure(s)** (PDB): [7ZW1](https://www.rcsb.org/structure/7ZW1).

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-10-28.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-10-28 |

## Associated conditions {#conditions}

[PRPH2-related disorder](https://sugi.bio/atlas/disease/prph2-related-disorder/).

**Reported phenotype names (ClinVar):** PRPH2-related disorder, PRPH2-related disorders, PRPH2-related condition.

## Same-residue context {#hotspot}

Residue **331** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PRPH2 p.Gln331Ter](/variant/prph2-p-gln331ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PRPH2 variant pages (same residue, condition, or type): [PRPH2 p.Gln331Ter](/variant/prph2-p-gln331ter), [PRPH2 p.Gln331=](/variant/prph2-p-gln331), [PRPH2 p.Asn136fs](/variant/prph2-p-asn136fs), [PRPH2 p.Asp50fs](/variant/prph2-p-asp50fs), [PRPH2 p.Asp87fs](/variant/prph2-p-asp87fs), [PRPH2 p.Gln132fs](/variant/prph2-p-gln132fs), [PRPH2 p.Gly38fs](/variant/prph2-p-gly38fs), [PRPH2 p.Leu290fs](/variant/prph2-p-leu290fs).

### 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 1053626). 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.*