Is PDE6C p.Glu253Asp (c.759A>C) pathogenic?

PDE6C p.Glu253Asp (c.759A>C) is classified Uncertain significance in PDE6C (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-27). AlphaMissense: likely pathogenic (0.8489); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PDE6C p.Glu253Asp (c.759A>C)?

PDE6C p.Glu253Asp (c.759A>C) is associated with Inborn genetic diseases (ClinVar).

How common is PDE6C p.Glu253Asp (c.759A>C) in the general population?

PDE6C p.Glu253Asp (c.759A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PDE6C p.Glu253Asp (c.759A>C)?

AlphaMissense predicts likely pathogenic (score 0.8489) — an in-silico prediction, not a clinical call.

PDE6C p.Glu253Asp

c.759A>C · VCV3416291

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8489 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8489	likely pathogenic
REVEL	0.373	indeterminate
SaProt	LLR -8.09	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 1.8	GERP 0.045, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 53 kb · p 8.6e-05 · regional, not allelic
Overall
CADD	22.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PDE6C
Protein: p.Glu253Asp
Coding: c.759A>C
MANE Select: NM_006204
Type: single nucleotide variant
Location: chr10:93621967 (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 253: the gaf 2 domain

Full PDE6C 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

PDE6C p.Ala264Val Uncertain significance ★★ ⚠ same condition
PDE6C p.Ala462Val Uncertain significance ★★ ⚠ same condition
PDE6C p.Ala668Thr Uncertain significance ★★ ⚠ same condition
PDE6C p.Arg527Gln Uncertain significance ★★ ⚠ same condition
PDE6C p.Arg95Cys Uncertain significance ★★ ⚠ same condition
PDE6C p.Asn16Lys Uncertain significance ★★ ⚠ same condition
PDE6C p.Asn611Ser Uncertain significance ★★ ⚠ same condition
PDE6C p.Asp367Glu 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/pde6c-p-glu253asp (accessed [today's date]).

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