Is CNGA1 p.Val449Phe (c.1345G>T) pathogenic?

CNGA1 p.Val449Phe (c.1345G>T) is classified Uncertain significance in CNGA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-07). AlphaMissense: likely pathogenic (0.7941); Very rare (popmax 0.00407%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CNGA1 p.Val449Phe (c.1345G>T)?

CNGA1 p.Val449Phe (c.1345G>T) is associated with Inborn genetic diseases (ClinVar).

How common is CNGA1 p.Val449Phe (c.1345G>T) in the general population?

CNGA1 p.Val449Phe (c.1345G>T) is very rare (popmax 0.00407%, nfe) (gnomAD).

What do computational predictors say about CNGA1 p.Val449Phe (c.1345G>T)?

AlphaMissense predicts likely pathogenic (score 0.7941) — an in-silico prediction, not a clinical call.

CNGA1 p.Val449Phe

c.1345G>T · VCV3494315

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7941 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00407%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7941	likely pathogenic
REVEL	0.861	moderately pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 4.3, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 16 kb · p 0.011 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V453F vs ClinVar V449F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00407% European (non-Finnish) · 48/1,180,014 alleles

Filtering AF 0.00315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00342% 50/1,461,868 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00407%	24,584
Remaining individualsnot grpmax-eligible	0.0032%	31,253

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: CNGA1
Protein: p.Val449Phe
Coding: c.1345G>T
MANE Select: NM_001379270
Type: single nucleotide variant
Location: chr4:47937137 (GRCh38)
Gene constraint: LOEUF 0.779 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.88 · 19 PDB
Residue 449: the 'c-linker' region; an α-helix

Full CNGA1 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

CNGA1 p.Val449Ala Uncertain significance ★ ⚠ same residue
CNGA1 p.Ala408Val Uncertain significance ★★ ⚠ same condition
CNGA1 p.Ala524Ser Uncertain significance ★★ same condition
CNGA1 p.Arg510Gln Uncertain significance ★★ ⚠ same condition
CNGA1 p.Arg625Gln Uncertain significance ★★ ⚠ same condition
CNGA1 p.Arg639Gln Uncertain significance ★★ same condition
CNGA1 p.Asp245Tyr Uncertain significance ★★ ⚠ same condition
CNGA1 p.Asp536Asn 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/cnga1-p-val449phe (accessed [today's date]).

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