Is PDE6C p.Arg557Ter (c.1669C>T) pathogenic?

PDE6C p.Arg557Ter (c.1669C>T) is classified Pathogenic/Likely pathogenic in PDE6C (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-04). Very rare (popmax 0.00136%, nfe); Associated with PDE6C-related disorder.

What condition is associated with PDE6C p.Arg557Ter (c.1669C>T)?

PDE6C p.Arg557Ter (c.1669C>T) is associated with PDE6C-related disorder, cone dystrophy 4, inherited retinal dystrophy (ClinVar).

How common is PDE6C p.Arg557Ter (c.1669C>T) in the general population?

PDE6C p.Arg557Ter (c.1669C>T) is very rare (popmax 0.00136%, nfe) (gnomAD).

PDE6C p.Arg557Ter

c.1669C>T · rs781699886 · VCV1069941

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Conditions

PDE6C-related disorder

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 13 of 22
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.3, phastCons 1
Overall
CADD	38.0	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

Grpmax group 0.00136% European (non-Finnish) · 16/1,179,658 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00116% 17/1,461,466 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00136%	73,728
South Asian	0.0011%	91,066

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.Arg557Ter
Coding: c.1669C>T
MANE Select: NM_006204
dbSNP: rs781699886
Type: single nucleotide variant
Location: chr10:93640489 (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 557: 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

PDE6C-related disorder

Also linked: cone dystrophy 4 inherited retinal dystrophy

Similar variants

PDE6C p.Arg557Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
PDE6C c.1004+1G>A Pathogenic/Likely pathogenic ★★ same condition
PDE6C c.2283+1G>T Pathogenic/Likely pathogenic ★★ same condition
PDE6C c.481-1G>A Likely pathogenic ★★ same condition
PDE6C c.939+2T>G Pathogenic/Likely pathogenic ★★ same condition
PDE6C c.939+5G>A Pathogenic/Likely pathogenic ★★ same condition
PDE6C p.Arg104Trp Pathogenic/Likely pathogenic ★★ same condition
PDE6C p.Arg238Ter 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-arg557ter (accessed [today's date]).

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