Is PDE6C p.Leu635Pro (c.1904T>C) pathogenic?

PDE6C p.Leu635Pro (c.1904T>C) is classified Uncertain significance in PDE6C (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-30). AlphaMissense: likely pathogenic (0.9977); Very rare (popmax 0.0011%, sas).

How common is PDE6C p.Leu635Pro (c.1904T>C) in the general population?

PDE6C p.Leu635Pro (c.1904T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about PDE6C p.Leu635Pro (c.1904T>C)?

AlphaMissense predicts likely pathogenic (score 0.9977) — an in-silico prediction, not a clinical call.

PDE6C p.Leu635Pro

c.1904T>C · rs747466783 · VCV1488752

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9977	likely pathogenic · top 2% in PDE6C
REVEL	0.932	strongly pathogenic-leaning
SaProt	LLR -14.47	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 53 kb · p 8.6e-05 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0011% South Asian · 1/90,906 alleles

Overall 6.88e-05% 1/1,452,942 alleles · very rare

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.Leu635Pro
Coding: c.1904T>C
MANE Select: NM_006204
dbSNP: rs747466783
Type: single nucleotide variant
Location: chr10:93646016 (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 635: a UniProt-annotated variant site (in achm5); the pdease domain; an α-helix

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

Similar variants

PDE6C p.Leu635Arg Uncertain significance ★ ⚠ same residue
PDE6C p.Leu635= Likely benign ★ 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
PDE6C c.939+5G>A 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-leu635pro (accessed [today's date]).

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