Is PDE6C p.Val9Met (c.25G>A) pathogenic?

PDE6C p.Val9Met (c.25G>A) is classified Uncertain significance in PDE6C (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-05). AlphaMissense: ambiguous (0.3964); Ultra-rare (popmax 0.0154%, sas).

How common is PDE6C p.Val9Met (c.25G>A) in the general population?

PDE6C p.Val9Met (c.25G>A) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about PDE6C p.Val9Met (c.25G>A)?

AlphaMissense predicts ambiguous (score 0.3964) — an in-silico prediction, not a clinical call.

PDE6C p.Val9Met

c.25G>A · rs750739971 · VCV850830

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3964 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Computational evidence

Protein change
AlphaMissense	0.3964	ambiguous
REVEL	0.523	indeterminate
SaProt	LLR -12.13	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 53 kb · p 8.6e-05 · regional, not allelic
Overall
CADD	25.5	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 0.0154% South Asian · 14/91,082 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00192% 31/1,613,954 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,506
East Asian	0.00891%	11,223
African / African-American	0.00534%	18,733
Admixed American	0.00167%	60,000
Remaining individualsnot grpmax-eligible	0.0016%	62,464
Finnishnot grpmax-eligible	0.00156%	64,046
European (non-Finnish)	0.000508%	196,675

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.Val9Met
Coding: c.25G>A
MANE Select: NM_006204
dbSNP: rs750739971
Type: single nucleotide variant
Location: chr10:93612750 (GRCh38)
Gene constraint: LOEUF 0.976 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.53 · 7 PDB

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

Similar variants

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
PDE6C p.Arg238Ter 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-val9met (accessed [today's date]).

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