Is PDE6C p.Glu329Ala (c.986A>C) pathogenic?

PDE6C p.Glu329Ala (c.986A>C) is classified Conflicting classifications of pathogenicity in PDE6C (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-10-25). AlphaMissense: likely pathogenic (0.8492); Rare (popmax 0.123%, eas); Associated with cone dystrophy 4.

What condition is associated with PDE6C p.Glu329Ala (c.986A>C)?

PDE6C p.Glu329Ala (c.986A>C) is associated with cone dystrophy 4, achromatopsia (ClinVar).

How common is PDE6C p.Glu329Ala (c.986A>C) in the general population?

PDE6C p.Glu329Ala (c.986A>C) is rare (popmax 0.123%, eas) (gnomAD).

How is Progressive cone dystrophy inherited?

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

What do computational predictors say about PDE6C p.Glu329Ala (c.986A>C)?

AlphaMissense predicts likely pathogenic (score 0.8492) — an in-silico prediction, not a clinical call.

PDE6C p.Glu329Ala

c.986A>C · rs758391651 · VCV301628

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8492 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.123%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cone dystrophy 4

Computational evidence

Protein change
AlphaMissense	0.8492	likely pathogenic
REVEL	0.589	indeterminate
SaProt	LLR -8.01	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 2.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 53 kb · p 8.6e-05 · regional, not allelic
Overall
CADD	27.7	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 0.123% East Asian · 55/44,856 alleles

Filtering AF 0.0967% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0874%

Overall 0.00573% 92/1,604,930 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.123%	816
Ashkenazi Jewishnot grpmax-eligible	0.0948%	1,055
Remaining individualsnot grpmax-eligible	0.0113%	8,885
European (non-Finnish)	0.000171%	585,854

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.Glu329Ala
Coding: c.986A>C
MANE Select: NM_006204
dbSNP: rs758391651
Type: single nucleotide variant
Location: chr10:93626686 (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 329: a UniProt-annotated variant site (in achm5); the gaf 2 domain

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

Disease context

cone dystrophy 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: achromatopsia

For Progressive cone dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adult

Similar variants

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
PDE6C p.Arg29Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
PDE6C p.Arg527Ter 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-glu329ala (accessed [today's date]).

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