Is PRPH2 p.Arg46Ter (c.136C>T) pathogenic?

PRPH2 p.Arg46Ter (c.136C>T) is classified Pathogenic/Likely pathogenic in PRPH2 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2025-09-11). Ultra-rare (popmax 0.0164%, mid); Associated with PRPH2-related disorder.

What condition is associated with PRPH2 p.Arg46Ter (c.136C>T)?

PRPH2 p.Arg46Ter (c.136C>T) is associated with PRPH2-related disorder, patterned macular dystrophy 1, retinitis pigmentosa 7 (ClinVar).

How common is PRPH2 p.Arg46Ter (c.136C>T) in the general population?

PRPH2 p.Arg46Ter (c.136C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

PRPH2 p.Arg46Ter

c.136C>T · rs61755771 · VCV13179

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

Consequence

nonsense (stop-gain)

predicted LoF

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.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 3
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.4	GERP 1.7, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00062% 10/1,614,002 alleles · ultra-rare exomes 7/1,461,890 · genomes 3/152,112 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.00401%	24,969
Finnishnot grpmax-eligible	0.00312%	32,013
European (non-Finnish)	0.000339%	295,008

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.Arg46Ter
Coding: c.136C>T
MANE Select: NM_000322
dbSNP: rs61755771
Type: single nucleotide variant
Location: chr6:42722199 (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

Also linked: patterned macular dystrophy 1 retinitis pigmentosa 7 choroidal dystrophy, central areolar 2 patterned dystrophy of the retinal pigment epithelium inherited retinal dystrophy Stargardt disease

Similar variants

PRPH2 p.Arg46Gln Uncertain significance ★★ same residue
PRPH2 p.Arg46Pro Uncertain significance ★ same residue
PRPH2 c.581+1G>A Pathogenic ★★ same condition
PRPH2 c.582-1G>A Pathogenic/Likely pathogenic ★★ same condition
PRPH2 c.582-2A>T 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

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-arg46ter (accessed [today's date]).

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