Is PRPH2 p.Pro221= (c.663C>T) pathogenic?

PRPH2 p.Pro221= (c.663C>T) is classified Likely benign in PRPH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-16). Very rare (popmax 0.00223%, eas); Associated with PRPH2-related disorder.

What condition is associated with PRPH2 p.Pro221= (c.663C>T)?

PRPH2 p.Pro221= (c.663C>T) is associated with PRPH2-related disorder (ClinVar).

How common is PRPH2 p.Pro221= (c.663C>T) in the general population?

PRPH2 p.Pro221= (c.663C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

PRPH2 p.Pro221=

c.663C>T · rs747689734 · VCV1128045

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

PRPH2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP -1.7, phastCons 1
Overall
CADD	13.54	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,886 alleles

Overall 0.000248% 4/1,614,078 alleles · very rare exomes 3/1,461,892 · genomes 1/152,186 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,886
African / African-American	0.00133%	74,928
South Asian	0.0011%	91,082
European (non-Finnish)	8.47e-05%	1,180,044

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.Pro221=
Coding: c.663C>T
MANE Select: NM_000322
dbSNP: rs747689734
Type: single nucleotide variant
Location: chr6:42704530 (GRCh38)
Gene constraint: LOEUF 0.773 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 1 PDB
Residue 221: a UniProt-annotated variant site (in cacd2)

Full PRPH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PRPH2-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRPH2 p.Pro221Ala Likely pathogenic ★ same residue
PRPH2 p.Pro221Arg Likely pathogenic ★ same residue
PRPH2 p.Pro221_Cys222del Likely pathogenic ★ same residue
PRPH2 p.Pro221Leu Pathogenic/Likely pathogenic ★★ same residue
PRPH2 p.Pro221Ser Uncertain significance ★ same residue
PRPH2 c.582-1G>A Pathogenic/Likely pathogenic ★★ same condition
PRPH2 c.828+1G>A Pathogenic ★★ same condition
PRPH2 c.828+1G>T Pathogenic ★★ same condition

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-pro221 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown