Is PRPH p.Ala109Val (c.326C>T) pathogenic?

PRPH p.Ala109Val (c.326C>T) is classified Uncertain significance in PRPH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely pathogenic (0.6577); Ultra-rare (popmax 0.019%, amr); Associated with Inborn genetic diseases.

What condition is associated with PRPH p.Ala109Val (c.326C>T)?

PRPH p.Ala109Val (c.326C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PRPH p.Ala109Val (c.326C>T) in the general population?

PRPH p.Ala109Val (c.326C>T) is ultra-rare (popmax 0.019%, amr) (gnomAD).

What do computational predictors say about PRPH p.Ala109Val (c.326C>T)?

AlphaMissense predicts likely pathogenic (score 0.6577) — an in-silico prediction, not a clinical call.

PRPH p.Ala109Val

c.326C>T · rs756599531 · VCV2465101

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6577 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.019%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6577	likely pathogenic
REVEL	0.921	moderately pathogenic-leaning
SaProt	LLR -12.21	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 3,149 bp · p 0.024 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.019% Admixed American · 11/57,934 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00821%

Overall 0.00219% 35/1,598,866 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.019%	5,267
Remaining individualsnot grpmax-eligible	0.00485%	20,635
European (non-Finnish)	0.00179%	55,863

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.Ala109Val
Coding: c.326C>T
MANE Select: NM_006262
dbSNP: rs756599531
Type: single nucleotide variant
Location: chr12:49295526 (GRCh38)
Gene constraint: LOEUF 1.161 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.24
Residue 109: the if rod domain; the 'coil 1a' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRPH p.Glu233Lys Uncertain significance ★★ ⚠ same condition
PRPH p.Ile419Met Uncertain significance ★★ ⚠ same condition
PRPH p.Ala132Thr Uncertain significance ★ ⚠ same condition
PRPH p.Ala132Val Uncertain significance ★ ⚠ same condition
PRPH p.Ala193Glu Uncertain significance ★ ⚠ same condition
PRPH p.Ala193Gly Uncertain significance ★ ⚠ same condition
PRPH p.Ala49Val Uncertain significance ★ ⚠ same condition
PRPH p.Ala67Pro Uncertain significance ★ ⚠ 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/prph-p-ala109val (accessed [today's date]).

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