# NM_000322.5(PRPH2):c.628C>T (p.Pro210Ser)

https://sugi.bio/variant/prph2-p-pro210ser

## Summary

**PRPH2 p.Pro210Ser (c.628C>T)** is classified **Pathogenic/Likely pathogenic** in PRPH2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-26). Absent from gnomAD v4.1; Associated with PRPH2-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs61755797 · 7 submitters · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PRPH2 gene that is considered likely disease-causing, submitted by 7 submitters, 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.Pro210Ser |
| Coding change (HGVS c.) | c.628C>T |
| MANE Select transcript | [NM_000322](https://www.ncbi.nlm.nih.gov/nuccore/NM_000322) |
| dbSNP | [rs61755797](https://www.ncbi.nlm.nih.gov/snp/rs61755797/) |
| Variant type | single nucleotide variant |
| Location | chr6:42704565-42704565 (GRCh38) |
| ClinVar | [VCV98686](https://www.ncbi.nlm.nih.gov/clinvar/variation/98686/) |

**All HGVS expressions:** `NC_000006.11:g.42672303G>A`, `NC_000006.12:g.42704565G>A`, `NG_009176.2:g.23056C>T`, `NM_000322.5:c.628C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.22) — consistent with the pathogenic call
- Conservation: phyloP 11.648, GERP 1.55, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 33.0**. 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.*
- Regional missense constraint: **o/e 0.98** across the covering region of the MANE Select transcript (42,698,298–42,722,334), spanning 24,036 bp. Chi-square p 0.64. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.02**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.02**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **210** lies in a UniProt-annotated variant site (in rp7; decreased protein expression); a UniProt-annotated variant site (in mdpt1 and rp7; also in adult-onset foveomacular dystrophy with choroidal neovascularization); a UniProt-annotated variant site (in rp7).

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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-26.

**Submitter consensus:** conflicting (4 Likely pathogenic, 2 Pathogenic, 1 not provided).

**Submission history:** 7 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Retina International | not provided | no classification provided | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-26 |
| CeGaT Center for Human Genetics Tuebingen | Likely pathogenic | criteria provided, single submitter | clinical testing | 2017-05-01 |
| Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Likely pathogenic | no assertion criteria provided | research | 2018-04-01 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-09-02 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-06-17 |
| Leiden Open Variation Database | Likely pathogenic | no assertion criteria provided | curation | 2021-04-06 |

## Associated conditions {#conditions}

[PRPH2-related disorder](https://sugi.bio/atlas/disease/prph2-related-disorder/), [vitelliform macular dystrophy 2](https://sugi.bio/atlas/disease/vitelliform-macular-dystrophy-2/).

**Reported phenotype names (ClinVar):** PRPH2-related disorder, not provided, Vitelliform macular dystrophy 2, PRPH2-related disorders, PRPH2-related condition, MACULAR DEGENERATION, POLYMORPHIC VITELLINE, Best Vitelliform Macular Dystrophy (BVMD), VITELLIFORM MACULAR DYSTROPHY, EARLY-ONSET, VITELLIFORM MACULAR DYSTROPHY, JUVENILE-ONSET, Best vitelliform macular dystrophy, multifocal.

## Same-residue context {#hotspot}

Residue **210** carries **4 other pathogenic ClinVar variants** — a recurrently-mutated position: [PRPH2 p.Pro210Ala](/variant/prph2-p-pro210ala), [PRPH2 p.Pro210Arg](/variant/prph2-p-pro210arg), [PRPH2 p.Pro210His](/variant/prph2-p-pro210his), [PRPH2 p.Pro210Leu](/variant/prph2-p-pro210leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PRPH2 variant pages (same residue, condition, or type): [PRPH2 p.Pro210Ala](/variant/prph2-p-pro210ala), [PRPH2 p.Pro210Arg](/variant/prph2-p-pro210arg), [PRPH2 p.Pro210Leu](/variant/prph2-p-pro210leu), [PRPH2 p.Pro210=](/variant/prph2-p-pro210), [PRPH2 p.Pro210His](/variant/prph2-p-pro210his), [PRPH2 c.582-1G>A](/variant/prph2-c-582-minus-1g-a), [PRPH2 c.582-1G>C](/variant/prph2-c-582-minus-1g-c), [PRPH2 c.828+1G>A](/variant/prph2-c-828-plus-1g-a).

### 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 98686). 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.*