# NM_000322.5(PRPH2):c.423_424dup (p.Arg142fs)

https://sugi.bio/variant/prph2-p-arg142fs

## Summary

**PRPH2 p.Arg142fs (c.423_424dup)** is classified **Pathogenic** in PRPH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-01). Associated with patterned macular dystrophy 1.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## 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 patterned macular dystrophy 1.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018237/index) · [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.Arg142fs |
| Coding change (HGVS c.) | c.423_424dup |
| MANE Select transcript | [NM_000322](https://www.ncbi.nlm.nih.gov/nuccore/NM_000322) |
| Variant type | Duplication |
| Location | chr6:42721910-42721911 (GRCh38) |
| ClinVar | [VCV4532240](https://www.ncbi.nlm.nih.gov/clinvar/variation/4532240/) |

**All HGVS expressions:** `NC_000006.11:g.42689649_42689650dup`, `NC_000006.12:g.42721911_42721912dup`, `NG_009176.2:g.5709_5710dup`, `NM_000322.5:c.423_424dup`

## 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 5.895, GERP 1.81, 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 exon 1 of 3**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

Residue **142** lies in a UniProt-annotated variant site (in rp7; also found in a patient with central areolar choroidal dystrophy).

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 2025-12-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-01 |

## Associated conditions {#conditions}

[patterned macular dystrophy 1](https://sugi.bio/atlas/disease/patterned-macular-dystrophy-1/).

**Reported phenotype names (ClinVar):** Patterned macular dystrophy 1, BUTTERFLY DYSTROPHY OF RETINAL PIGMENT EPITHELIUM, MACULAR DYSTROPHY, BUTTERFLY-SHAPED PIGMENTARY.

## Same-residue context {#hotspot}

Residue **142** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PRPH2 p.Arg142Trp](/variant/prph2-p-arg142trp). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PRPH2 variant pages (same residue, condition, or type): [PRPH2 p.Arg142Trp](/variant/prph2-p-arg142trp), [PRPH2 p.Ser125fs](/variant/prph2-p-ser125fs), [PRPH2 p.Ser289fs](/variant/prph2-p-ser289fs), [PRPH2 p.Arg142Gln](/variant/prph2-p-arg142gln), [PRPH2 p.Tyr141fs](/variant/prph2-p-tyr141fs), [PRPH2 c.828+3A>T](/variant/prph2-c-828-plus-3a-t), [PRPH2 c.829-4C>G](/variant/prph2-c-829-minus-4c-g), [PRPH2 p.Arg172Trp](/variant/prph2-p-arg172trp).

### 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 4532240). 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.*