Is PDE6C p.Ile331Val (c.991A>G) pathogenic?

PDE6C p.Ile331Val (c.991A>G) is classified Uncertain significance in PDE6C (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-11). AlphaMissense: likely pathogenic (0.6632); Ultra-rare (popmax 0.0107%, afr); Associated with Inborn genetic diseases.

What condition is associated with PDE6C p.Ile331Val (c.991A>G)?

PDE6C p.Ile331Val (c.991A>G) is associated with Inborn genetic diseases (ClinVar).

How common is PDE6C p.Ile331Val (c.991A>G) in the general population?

PDE6C p.Ile331Val (c.991A>G) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about PDE6C p.Ile331Val (c.991A>G)?

AlphaMissense predicts likely pathogenic (score 0.6632) — an in-silico prediction, not a clinical call.

PDE6C p.Ile331Val

c.991A>G · rs369628525 · VCV198191

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6632 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6632	likely pathogenic
REVEL	0.306	indeterminate
SaProt	LLR -5.50	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 2.2, 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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% African / African-American · 8/74,768 alleles

Filtering AF 0.00831% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00779%

Overall 0.00785% 126/1,605,988 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,346
European (non-Finnish)	0.00981%	10,197
Remaining individualsnot grpmax-eligible	0.00321%	31,112
Admixed American	0.00167%	59,992

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.Ile331Val
Coding: c.991A>G
MANE Select: NM_006204
dbSNP: rs369628525
Type: single nucleotide variant
Location: chr10:93626691 (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 331: 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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PDE6C p.Ala264Val Uncertain significance ★★ ⚠ same condition
PDE6C p.Ala462Val Uncertain significance ★★ ⚠ same condition
PDE6C p.Ala668Thr Uncertain significance ★★ same condition
PDE6C p.Arg527Gln Uncertain significance ★★ ⚠ same condition
PDE6C p.Arg95Cys Uncertain significance ★★ ⚠ same condition
PDE6C p.Asn16Lys Uncertain significance ★★ ⚠ same condition
PDE6C p.Asn611Ser Uncertain significance ★★ ⚠ same condition
PDE6C p.Asp367Glu Uncertain significance ★★ same condition

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-ile331val (accessed [today's date]).

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