Is PRPH2 p.Pro219Thr (c.655C>A) pathogenic?

PRPH2 p.Pro219Thr (c.655C>A) is classified Uncertain significance in PRPH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-20). Very rare (popmax 0.00267%, afr); Associated with PRPH2-related disorder.

What condition is associated with PRPH2 p.Pro219Thr (c.655C>A)?

PRPH2 p.Pro219Thr (c.655C>A) is associated with PRPH2-related disorder (ClinVar).

How common is PRPH2 p.Pro219Thr (c.655C>A) in the general population?

PRPH2 p.Pro219Thr (c.655C>A) is very rare (popmax 0.00267%, afr) (gnomAD).

PRPH2 p.Pro219Thr

c.655C>A · VCV4730650

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

PRPH2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.657	pathogenic-leaning
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	27.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,918 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,614,056 alleles · very rare exomes 2/1,461,888 · genomes 2/152,168 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,459
South Asian	0.0011%	91,088
European (non-Finnish)	8.47e-05%	1,180,027

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.Pro219Thr
Coding: c.655C>A
MANE Select: NM_000322
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)

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.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.Pro219fs Pathogenic ★ same residue
PRPH2 p.Pro219Ala Likely pathogenic ★ 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-pro219thr (accessed [today's date]).

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