Is PDE6A p.Arg652Cys (c.1954C>T) pathogenic?

PDE6A p.Arg652Cys (c.1954C>T) is classified Conflicting classifications of pathogenicity in PDE6A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-21). AlphaMissense: likely pathogenic (0.6552); Rare (popmax 0.613%, eas); Associated with retinitis pigmentosa.

What condition is associated with PDE6A p.Arg652Cys (c.1954C>T)?

PDE6A p.Arg652Cys (c.1954C>T) is associated with retinitis pigmentosa, inherited retinal dystrophy (ClinVar).

How common is PDE6A p.Arg652Cys (c.1954C>T) in the general population?

PDE6A p.Arg652Cys (c.1954C>T) is rare (popmax 0.613%, eas) (gnomAD).

How is Retinitis pigmentosa inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PDE6A p.Arg652Cys (c.1954C>T)?

AlphaMissense predicts likely pathogenic (score 0.6552) — an in-silico prediction, not a clinical call.

PDE6A p.Arg652Cys

c.1954C>T · rs199748187 · VCV351983

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6552 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.613%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.6552	likely pathogenic
REVEL	0.563	indeterminate
SaProt	LLR -11.50	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 77 kb · p 0.94 · regional, not allelic
Overall
CADD	33.0	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 0.613% East Asian · 275/44,864 alleles

Filtering AF 0.553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.53%

Overall 0.0182% 293/1,613,722 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.613%	163
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0048%	20,832
African / African-American	0.004%	24,995
South Asian	0.00329%	30,359
European (non-Finnish)	0.000678%	147,467

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: PDE6A
Protein: p.Arg652Cys
Coding: c.1954C>T
MANE Select: NM_000440
dbSNP: rs199748187
Type: single nucleotide variant
Location: chr5:149884552 (GRCh38)
Gene constraint: LOEUF 0.888 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.80
Residue 652: the pdease domain

Full PDE6A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

retinitis pigmentosa — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: inherited retinal dystrophy

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

PDE6A p.Arg652His Uncertain significance ★★ ⚠ same residue
PDE6A c.1065+2T>A Pathogenic/Likely pathogenic ★★ same condition
PDE6A c.1407+1G>C Pathogenic/Likely pathogenic ★★ same condition
PDE6A c.1620+1G>A Pathogenic ★★ same condition
PDE6A c.1926+1G>A Pathogenic ★★ same condition
PDE6A c.1927-1G>C Pathogenic/Likely pathogenic ★★ same condition
PDE6A c.627+2T>G Pathogenic ★★ same condition
PDE6A c.998+1G>A 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/pde6a-p-arg652cys (accessed [today's date]).

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