Is PDE6C p.Ile392Val (c.1174A>G) pathogenic?

PDE6C p.Ile392Val (c.1174A>G) is classified Uncertain significance in PDE6C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-03). AlphaMissense: likely benign (0.1378); Ultra-rare (popmax 0.012%, afr).

How common is PDE6C p.Ile392Val (c.1174A>G) in the general population?

PDE6C p.Ile392Val (c.1174A>G) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about PDE6C p.Ile392Val (c.1174A>G)?

AlphaMissense predicts likely benign (score 0.1378) — an in-silico prediction, not a clinical call.

PDE6C p.Ile392Val

c.1174A>G · rs141384587 · VCV1004017

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1378 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1378	likely benign
REVEL	0.595	indeterminate
SaProt	LLR -7.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.1	GERP 1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 53 kb · p 8.6e-05 · regional, not allelic
Overall
CADD	24.4	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 0.012% African / African-American · 9/74,934 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.000867% 14/1,614,018 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,326
East Asian	0.00223%	44,878
Admixed American	0.00167%	60,014
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.000169%	589,995

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.Ile392Val
Coding: c.1174A>G
MANE Select: NM_006204
dbSNP: rs141384587
Type: single nucleotide variant
Location: chr10:93634812 (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 392: 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.Ile392= 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-ile392val (accessed [today's date]).

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