Is PDE6C p.Leu100Pro (c.299T>C) pathogenic?

PDE6C p.Leu100Pro (c.299T>C) is classified Uncertain significance in PDE6C (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-26). AlphaMissense: ambiguous (0.4932); Very rare (popmax 0.004%, afr).

How common is PDE6C p.Leu100Pro (c.299T>C) in the general population?

PDE6C p.Leu100Pro (c.299T>C) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about PDE6C p.Leu100Pro (c.299T>C)?

AlphaMissense predicts ambiguous (score 0.4932) — an in-silico prediction, not a clinical call.

PDE6C p.Leu100Pro

c.299T>C · rs372972245 · VCV1951941

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4932 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Computational evidence

Protein change
AlphaMissense	0.4932	ambiguous
REVEL	0.384	indeterminate
SaProt	LLR -13.67	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.49	GERP -1.6
Regional constraint	o/e 0.88	unconstrained · MANE · 53 kb · p 8.6e-05 · regional, not allelic
Overall
CADD	17.77	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

Grpmax group 0.004% African / African-American · 3/74,930 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00197% 3/152,206 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.Leu100Pro
Coding: c.299T>C
MANE Select: NM_006204
dbSNP: rs372972245
Type: single nucleotide variant
Location: chr10:93613024 (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 100: the gaf 1 domain; a β-strand

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

Similar variants

PDE6C p.Leu100= 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
PDE6C p.Arg104Trp 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-leu100pro (accessed [today's date]).

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