Is PRPH2 p.Leu261Phe (c.781C>T) pathogenic?

PRPH2 p.Leu261Phe (c.781C>T) is classified Conflicting classifications of pathogenicity in PRPH2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-05). Ultra-rare (popmax 0.0164%, mid); Associated with PRPH2-related disorder.

What condition is associated with PRPH2 p.Leu261Phe (c.781C>T)?

PRPH2 p.Leu261Phe (c.781C>T) is associated with PRPH2-related disorder (ClinVar).

How common is PRPH2 p.Leu261Phe (c.781C>T) in the general population?

PRPH2 p.Leu261Phe (c.781C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

PRPH2 p.Leu261Phe

c.781C>T · rs150381599 · VCV1091067

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

PRPH2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.401	indeterminate
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.4	GERP 0.37, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 24 kb · p 0.64 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.00256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00553% 89/1,610,458 alleles · ultra-rare exomes 81/1,458,310 · genomes 8/152,148 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.105%	951
Remaining individualsnot grpmax-eligible	0.0224%	4,455
Middle Easterngrpmax	0.0164%	6,080
European (non-Finnish)	0.00339%	29,464
Admixed American	0.00169%	59,194
African / African-American	0.00134%	74,894
South Asian	0.00111%	90,434

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu261Phe
Coding: c.781C>T
MANE Select: NM_000322
dbSNP: rs150381599
Type: single nucleotide variant
Location: chr6:42704412 (GRCh38)
Gene constraint: LOEUF 0.773 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 1 PDB

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.Leu261Pro Uncertain significance ★ same residue
PRPH2 p.Leu261= Likely benign ★ 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
PRPH2 c.828+2T>C Pathogenic/Likely pathogenic ★★ same condition
PRPH2 c.828+3A>T Pathogenic ★★ same condition
PRPH2 p.Arg142Trp Pathogenic/Likely 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-leu261phe (accessed [today's date]).

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