Is PDE6A p.Ala364Val (c.1091C>T) pathogenic?

PDE6A p.Ala364Val (c.1091C>T) is classified Uncertain significance in PDE6A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-31). AlphaMissense: likely benign (0.1054); Very rare (popmax 0.0022%, sas).

How common is PDE6A p.Ala364Val (c.1091C>T) in the general population?

PDE6A p.Ala364Val (c.1091C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about PDE6A p.Ala364Val (c.1091C>T)?

AlphaMissense predicts likely benign (score 0.1054) — an in-silico prediction, not a clinical call.

PDE6A p.Ala364Val

c.1091C>T · rs200858325 · VCV1413022

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1054 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1054	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -8.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP -1.3, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 77 kb · p 0.94 · regional, not allelic
Overall
CADD	23.8	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 0.0022% South Asian · 2/91,074 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000616% 9/1,461,522 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,537
European (non-Finnish)	0.000593%	168,530

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.Ala364Val
Coding: c.1091C>T
MANE Select: NM_000440
dbSNP: rs200858325
Type: single nucleotide variant
Location: chr5:149903670 (GRCh38)
Gene constraint: LOEUF 0.888 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.80
Residue 364: the gaf 2 domain

Full PDE6A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDE6A p.Ala364= Likely benign ★★ same residue
PDE6A p.Ala364Glu Uncertain significance ★ same residue
PDE6A c.1065+2T>A Pathogenic/Likely pathogenic ★★ same type
PDE6A c.1263+1G>T Pathogenic/Likely pathogenic ★★ same type
PDE6A c.1407+1G>C Pathogenic/Likely pathogenic ★★ same type
PDE6A c.1620+1G>A Pathogenic ★★ same type
PDE6A c.1620+2T>A Pathogenic/Likely pathogenic ★★ same type
PDE6A c.1926+1G>A 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/pde6a-p-ala364val (accessed [today's date]).

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