Is PDE6A p.Ile449Val (c.1345A>G) pathogenic?

PDE6A p.Ile449Val (c.1345A>G) is classified Uncertain significance in PDE6A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-18). AlphaMissense: likely benign (0.0782); Very rare (popmax 0.00212%, nfe).

How common is PDE6A p.Ile449Val (c.1345A>G) in the general population?

PDE6A p.Ile449Val (c.1345A>G) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about PDE6A p.Ile449Val (c.1345A>G)?

AlphaMissense predicts likely benign (score 0.0782) — an in-silico prediction, not a clinical call.

PDE6A p.Ile449Val

c.1345A>G · rs2480574257 · VCV2120737

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0782 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0782	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -5.96	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 0.89	phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 77 kb · p 0.94 · regional, not allelic
Overall
CADD	18.28	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 0.00212% European (non-Finnish) · 25/1,179,400 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00171% 25/1,461,106 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.Ile449Val
Coding: c.1345A>G
MANE Select: NM_000440
dbSNP: rs2480574257
Type: single nucleotide variant
Location: chr5:149898425 (GRCh38)
Gene constraint: LOEUF 0.888 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.80

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

Similar variants

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
PDE6A c.1927-1G>C Pathogenic/Likely pathogenic ★★ same type
PDE6A c.2027+2T>G 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/pde6a-p-ile449val (accessed [today's date]).

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