Is PDE6C p.Val69Met (c.205G>A) pathogenic?

PDE6C p.Val69Met (c.205G>A) is classified Conflicting classifications of pathogenicity in PDE6C (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-01). AlphaMissense: likely benign (0.087); Rare (popmax 0.153%, sas).

How common is PDE6C p.Val69Met (c.205G>A) in the general population?

PDE6C p.Val69Met (c.205G>A) is rare (popmax 0.153%, sas) (gnomAD).

What do computational predictors say about PDE6C p.Val69Met (c.205G>A)?

AlphaMissense predicts likely benign (score 0.087) — an in-silico prediction, not a clinical call.

PDE6C p.Val69Met

c.205G>A · rs568930062 · VCV193332

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.087 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.153%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.087	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -7.99	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.8	GERP -4.1
Regional constraint	o/e 0.88	unconstrained · MANE · 53 kb · p 8.6e-05 · regional, not allelic
Overall
CADD	0.009	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 0.153% South Asian · 139/91,078 alleles

Filtering AF 0.132% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.124%

Overall 0.012% 193/1,613,996 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.153%	655
Admixed American	0.0183%	5,457
Remaining individualsnot grpmax-eligible	0.0064%	15,625
East Asian	0.00446%	22,436
African / African-American	0.004%	25,014
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
European (non-Finnish)	0.0028%	35,757

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.Val69Met
Coding: c.205G>A
MANE Select: NM_006204
dbSNP: rs568930062
Type: single nucleotide variant
Location: chr10:93612930 (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 69: 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.Val69Ala Uncertain significance ★ same residue
PDE6C p.Val69= 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

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-val69met (accessed [today's date]).

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