Is PRPH p.Arg9Gln (c.26G>A) pathogenic?

PRPH p.Arg9Gln (c.26G>A) is classified Benign in PRPH (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1125); Common (popmax 5.84%, mid) — too common for a highly-penetrant pathogenic allele; Associated with amyotrophic lateral sclerosis type 1.

What condition is associated with PRPH p.Arg9Gln (c.26G>A)?

PRPH p.Arg9Gln (c.26G>A) is associated with amyotrophic lateral sclerosis type 1 (ClinVar).

What do computational predictors say about PRPH p.Arg9Gln (c.26G>A)?

AlphaMissense predicts likely benign (score 0.1125) — an in-silico prediction, not a clinical call.

PRPH p.Arg9Gln

Q: How common is PRPH p.Arg9Gln (c.26G>A) in the general population?

PRPH p.Arg9Gln (c.26G>A) is common (popmax 5.84%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.26G>A · rs57451017 · VCV66714

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1125 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.84%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis type 1

Computational evidence

Protein change
AlphaMissense	0.1125	likely benign
REVEL	0.206	benign-leaning
SaProt	LLR -7.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 3,149 bp · p 0.024 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.84% Middle Eastern · 354/6,058 alleles

Filtering AF 5.34% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.15%

Overall 1.18% 19,077/1,611,522 alleles · common exomes 17,536/1,459,214 · genomes 1,541/152,308 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	5.84%	17
South Asian	3.29%	30
Remaining individualsnot grpmax-eligible	1.62%	62
East Asian	1.54%	65
Ashkenazi Jewishnot grpmax-eligible	1.53%	65
Finnishnot grpmax-eligible	1.19%	84
European (non-Finnish)	1.03%	97
Admixed American	0.948%	105
African / African-American	0.224%	446

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: PRPH
Protein: p.Arg9Gln
Coding: c.26G>A
MANE Select: NM_006262
dbSNP: rs57451017
Type: single nucleotide variant
Location: chr12:49295226 (GRCh38)
Gene constraint: LOEUF 1.161 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.24
Residue 9: the 'head' region

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

Disease context

amyotrophic lateral sclerosis type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRPH p.Gln249Ter Likely pathogenic ★ same condition
PRPH p.Gln307Ter Likely pathogenic ★ same condition
PRPH c.607-1G>A Conflicting classifications of pathogenicity ★ same condition
PRPH p.His232Arg Uncertain significance ★ ⚠ same condition
PRPH p.Thr422Ala Uncertain significance ★ ⚠ same condition
PRPH p.Glu233Lys Uncertain significance ★★ ⚠ same type
PRPH p.Ile419Met Uncertain significance ★★ ⚠ same type
PRPH c.1267+58T>C Benign ★★ 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/prph-p-arg9gln (accessed [today's date]).

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