Is PDE6A p.Val188Ala (c.563T>C) pathogenic?

PDE6A p.Val188Ala (c.563T>C) is classified Uncertain significance in PDE6A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-12). AlphaMissense: ambiguous (0.3681); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with PDE6A p.Val188Ala (c.563T>C)?

PDE6A p.Val188Ala (c.563T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PDE6A p.Val188Ala (c.563T>C) in the general population?

PDE6A p.Val188Ala (c.563T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about PDE6A p.Val188Ala (c.563T>C)?

AlphaMissense predicts ambiguous (score 0.3681) — an in-silico prediction, not a clinical call.

PDE6A p.Val188Ala

c.563T>C · rs1028060531 · VCV2314004

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3681 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3681	ambiguous
REVEL	0.462	indeterminate
SaProt	LLR -11.27	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 77 kb · p 0.94 · 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 0.00267% African / African-American · 2/74,948 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,614,030 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: PDE6A
Protein: p.Val188Ala
Coding: c.563T>C
MANE Select: NM_000440
dbSNP: rs1028060531
Type: single nucleotide variant
Location: chr5:149934630 (GRCh38)
Gene constraint: LOEUF 0.888 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.80
Residue 188: the gaf 1 domain

Full PDE6A 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

PDE6A p.Ala766Gly Uncertain significance ★★ ⚠ same condition
PDE6A p.Arg236Leu Uncertain significance ★★ ⚠ same condition
PDE6A p.Arg237Cys Uncertain significance ★★ ⚠ same condition
PDE6A p.Arg237His Uncertain significance ★★ ⚠ same condition
PDE6A p.Arg257Gln Uncertain significance ★★ ⚠ same condition
PDE6A p.Arg267Cys Uncertain significance ★★ ⚠ same condition
PDE6A p.Arg306Gly Uncertain significance ★★ ⚠ same condition
PDE6A p.Arg554Cys 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/pde6a-p-val188ala (accessed [today's date]).

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