Is PDE6C p.Pro335Leu (c.1004C>T) pathogenic?

PDE6C p.Pro335Leu (c.1004C>T) is classified Uncertain significance in PDE6C (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-24). AlphaMissense: likely benign (0.1536); Very rare (popmax 0.00418%, nfe).

How common is PDE6C p.Pro335Leu (c.1004C>T) in the general population?

PDE6C p.Pro335Leu (c.1004C>T) is very rare (popmax 0.00418%, nfe) (gnomAD).

What do computational predictors say about PDE6C p.Pro335Leu (c.1004C>T)?

AlphaMissense predicts likely benign (score 0.1536) — an in-silico prediction, not a clinical call.

PDE6C p.Pro335Leu

c.1004C>T · rs777483878 · VCV852219

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1536 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00418%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1536	likely benign
REVEL	0.424	indeterminate
SaProt	LLR -6.83	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 53 kb · p 8.6e-05 · regional, not allelic
Overall
CADD	27.8	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 0.00418% European (non-Finnish) · 49/1,172,328 alleles

Filtering AF 0.0032% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00288%

Overall 0.00349% 56/1,605,578 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00418%	23,925
African / African-American	0.00401%	24,909
Admixed American	0.00333%	29,994
Remaining individualsnot grpmax-eligible	0.00161%	62,230
Finnishnot grpmax-eligible	0.00156%	64,004

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.Pro335Leu
Coding: c.1004C>T
MANE Select: NM_006204
dbSNP: rs777483878
Type: single nucleotide variant
Location: chr10:93626704 (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 335: a UniProt-annotated variant site (in achm5); the gaf 2 domain; a β-strand

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

Similar variants

PDE6C p.Pro335Gln Uncertain significance ★★ ⚠ same residue
PDE6C p.Pro335= Uncertain significance ★ same residue
PDE6C p.Pro335Ser Uncertain significance ★ same residue
PDE6C c.1004+1G>A Pathogenic/Likely pathogenic ★★ same type
PDE6C c.1269+1G>A Pathogenic/Likely pathogenic ★★ same type
PDE6C c.2283+1G>T Pathogenic/Likely pathogenic ★★ same type
PDE6C c.481-1G>A Likely pathogenic ★★ same type
PDE6C c.939+2T>G Pathogenic/Likely pathogenic ★★ same type

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-pro335leu (accessed [today's date]).

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