Is PDE6C p.Ile222Phe (c.664A>T) pathogenic?

PDE6C p.Ile222Phe (c.664A>T) is classified Uncertain significance in PDE6C (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-17). AlphaMissense: likely benign (0.1716); Very rare (popmax 0.000254%, nfe).

How common is PDE6C p.Ile222Phe (c.664A>T) in the general population?

PDE6C p.Ile222Phe (c.664A>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about PDE6C p.Ile222Phe (c.664A>T)?

AlphaMissense predicts likely benign (score 0.1716) — an in-silico prediction, not a clinical call.

PDE6C p.Ile222Phe

c.664A>T · rs1336988861 · VCV2094353

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1716 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1716	likely benign
REVEL	0.275	benign-leaning
SaProt	LLR -7.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.33	acceptor gain · deltas
Pangolin	Δ0.30	loss · gain 0.18 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP -1.7	GERP -4.1
Regional constraint	o/e 0.88	unconstrained · MANE · 53 kb · p 8.6e-05 · regional, not allelic
Overall
CADD	10.1	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 0.000254% European (non-Finnish) · 3/1,179,974 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,832 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.Ile222Phe
Coding: c.664A>T
MANE Select: NM_006204
dbSNP: rs1336988861
Type: single nucleotide variant
Location: chr10:93620921 (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 222: the gaf 1 domain; an α-helix

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

Similar variants

PDE6C p.Ile222Val 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
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-ile222phe (accessed [today's date]).

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