Is CNGA3 p.Pro592Ala (c.1774C>G) pathogenic?

CNGA3 p.Pro592Ala (c.1774C>G) is classified Conflicting classifications of pathogenicity in CNGA3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-07-01). AlphaMissense: ambiguous (0.5558); Very rare (popmax 0.000508%, nfe).

How common is CNGA3 p.Pro592Ala (c.1774C>G) in the general population?

CNGA3 p.Pro592Ala (c.1774C>G) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about CNGA3 p.Pro592Ala (c.1774C>G)?

AlphaMissense predicts ambiguous (score 0.5558) — an in-silico prediction, not a clinical call.

CNGA3 p.Pro592Ala

c.1774C>G · VCV3676112

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5558 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5558	ambiguous
REVEL	0.938	strongly pathogenic-leaning
SaProt	LLR -14.91	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 1,336 bp · p 0.34 · regional, not allelic
Overall
CADD	26.0	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 0.000508% European (non-Finnish) · 6/1,180,040 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00041% 6/1,461,838 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: CNGA3
Protein: p.Pro592Ala
Coding: c.1774C>G
MANE Select: NM_001298
Type: single nucleotide variant
Location: chr2:98396944 (GRCh38)
Gene constraint: LOEUF 1.126 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.33 · 10 PDB
Residue 592: an α-helix; the 'cyclic nucleotide-binding domain' region

Full CNGA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNGA3 p.Pro592Leu Pathogenic/Likely pathogenic ★★ same residue
CNGA3 p.Pro592= Likely benign ★★ same residue
CNGA3 c.216-1G>A Likely pathogenic ★★ same type
CNGA3 c.396-11C>G Pathogenic/Likely pathogenic ★★ same type
CNGA3 c.450-1G>A Pathogenic ★★ same type
CNGA3 p.Ala262Pro Likely pathogenic ★★ ⚠ same type
CNGA3 p.Ala318Thr Pathogenic ★★ same type
CNGA3 p.Ala469Thr 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/cnga3-p-pro592ala (accessed [today's date]).

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