Is PDE6C p.Trp731Ter (c.2192G>A) pathogenic?

PDE6C p.Trp731Ter (c.2192G>A) is classified Pathogenic/Likely pathogenic in PDE6C (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-23). Absent from gnomAD v4.1; Associated with cone dystrophy 4.

What condition is associated with PDE6C p.Trp731Ter (c.2192G>A)?

PDE6C p.Trp731Ter (c.2192G>A) is associated with cone dystrophy 4 (ClinVar).

How common is PDE6C p.Trp731Ter (c.2192G>A) in the general population?

PDE6C p.Trp731Ter (c.2192G>A) is absent from gnomAD v4.1 (gnomAD).

How is Progressive cone dystrophy inherited?

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

PDE6C p.Trp731Ter

c.2192G>A · rs1589705946 · VCV802622

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

cone dystrophy 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 18 of 22
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Overall
CADD	44.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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.Trp731Ter
Coding: c.2192G>A
MANE Select: NM_006204
dbSNP: rs1589705946
Type: single nucleotide variant
Location: chr10:93659151 (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 731: a UniProt-annotated variant site (in achm5); the pdease 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

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.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
PDE6C p.Arg557Ter 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-trp731ter (accessed [today's date]).

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