PRPH2 p.Pro219Ala
c.655C>G · rs749603273 · VCV2580761
Likely pathogenic
Single submitter
Classification
Likely pathogenic
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0165%, mid)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.572 | indeterminate |
|---|---|---|
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 0.6, phastCons 1 |
| Regional constraint | o/e 0.98 | unconstrained · MANE · 24 kb · p 0.64 · regional, not allelic |
| Overall | ||
| CADD | 26.7 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0165%
Middle Eastern · 1/6,062 alleles
Overall
0.000186%
3/1,614,174 alleles · ultra-rare
exomes 3/1,461,888 · genomes 0/152,286 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0165% | 6,062 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,506 |
| European (non-Finnish) | 8.47e-05% | 1,180,020 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- PRPH2
- Protein
- p.Pro219Ala
- Coding
- c.655C>G
- MANE Select
- NM_000322
- dbSNP
- rs749603273
- Type
- single nucleotide variant
- Location
- chr6:42704538 (GRCh38)
- Gene constraint
- LOEUF 0.773 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 87.56 · 1 PDB
- Residue 219
- a UniProt-annotated variant site (in some patients with macular dystrophy); a UniProt-annotated variant site (in rp7)
Similar variants
- PRPH2 p.Pro219Thr Uncertain significance ★★ same residue
- PRPH2 p.Pro219Arg Conflicting classifications of pathogenicity ★ same residue
- PRPH2 p.Pro219Ser Conflicting classifications of pathogenicity ★ same residue
- PRPH2 p.Pro219= Likely benign ★ same residue
- PRPH2 p.Pro219del Likely pathogenic ★ same residue
- PRPH2 p.Pro219fs Pathogenic ★ same residue
- PRPH2 c.581+1G>A Pathogenic ★★ same type
- PRPH2 c.582-1G>A Pathogenic/Likely pathogenic ★★ same type
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/prph2-p-pro219ala (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown