Is PDE6C p.Arg502His (c.1505G>A) pathogenic?

PDE6C p.Arg502His (c.1505G>A) is classified Uncertain significance in PDE6C (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-10-23). AlphaMissense: likely benign (0.077); Very rare (popmax 0.00333%, amr); Associated with achromatopsia.

What condition is associated with PDE6C p.Arg502His (c.1505G>A)?

PDE6C p.Arg502His (c.1505G>A) is associated with achromatopsia, cone dystrophy 4 (ClinVar).

How common is PDE6C p.Arg502His (c.1505G>A) in the general population?

PDE6C p.Arg502His (c.1505G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

How is Achromatopsia inherited?

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

What do computational predictors say about PDE6C p.Arg502His (c.1505G>A)?

AlphaMissense predicts likely benign (score 0.077) — an in-silico prediction, not a clinical call.

PDE6C p.Arg502His

c.1505G>A · rs779174659 · VCV301633

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.077 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

achromatopsia

Computational evidence

Protein change
AlphaMissense	0.077	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -6.27	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 0.18	GERP -3.1
Regional constraint	o/e 0.88	unconstrained · MANE · 53 kb · p 8.6e-05 · regional, not allelic
Overall
CADD	7.468	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00333% Admixed American · 2/59,986 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.0018% 29/1,613,940 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,993
African / African-American	0.00267%	37,453
South Asian	0.0022%	45,539
European (non-Finnish)	0.00186%	53,635
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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: PDE6C
Protein: p.Arg502His
Coding: c.1505G>A
MANE Select: NM_006204
dbSNP: rs779174659
Type: single nucleotide variant
Location: chr10:93640092 (GRCh38)
Gene constraint: LOEUF 0.976 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.53 · 7 PDB
Residue 502: a UniProt-annotated variant site (in achm5); the pdease domain; a turn

Full PDE6C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: cone dystrophy 4

For Achromatopsia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

PDE6C p.Arg502Cys Uncertain significance ★★ ⚠ same residue
PDE6C p.Arg502Gly Uncertain significance ★ ⚠ same residue
PDE6C c.1004+1G>A Pathogenic/Likely pathogenic ★★ same condition
PDE6C c.1269+1G>A Pathogenic/Likely pathogenic ★★ same condition
PDE6C c.2283+1G>T Pathogenic/Likely pathogenic ★★ same condition
PDE6C c.939+5G>A Pathogenic/Likely pathogenic ★★ same condition
PDE6C p.Arg238Ter Pathogenic/Likely pathogenic ★★ same condition
PDE6C p.Arg259Ter 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/pde6c-p-arg502his (accessed [today's date]).

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