Is CNGA3 p.Gln537fs (c.1609del) pathogenic?

CNGA3 p.Gln537fs (c.1609del) is classified Conflicting classifications of pathogenicity in CNGA3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-16). Very rare (popmax 0.005%, amr); Associated with achromatopsia 2.

What condition is associated with CNGA3 p.Gln537fs (c.1609del)?

CNGA3 p.Gln537fs (c.1609del) is associated with achromatopsia 2 (ClinVar).

How common is CNGA3 p.Gln537fs (c.1609del) in the general population?

CNGA3 p.Gln537fs (c.1609del) is very rare (popmax 0.005%, amr) (gnomAD).

How is Achromatopsia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CNGA3 p.Gln537fs

c.1609del · rs1293852552 · VCV1459175

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

achromatopsia 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (8 of 8) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,004 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000186% 3/1,614,100 alleles · very rare exomes 2/1,461,890 · genomes 1/152,210 · joint denominator

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.Gln537fs
Coding: c.1609del
MANE Select: NM_001298
dbSNP: rs1293852552
Type: Deletion
Location: chr2:98396777 (GRCh38)
Gene constraint: LOEUF 1.126 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.33 · 10 PDB
Residue 537: the 'cyclic nucleotide-binding domain' region

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

Disease context

achromatopsia 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Achromatopsia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

CNGA3 p.Ala411fs Pathogenic ★★ same condition
CNGA3 p.Asp507fs Pathogenic ★★ same condition
CNGA3 p.Leu390fs Likely pathogenic ★★ same condition
CNGA3 p.Asn26fs Pathogenic ★ same condition
CNGA3 p.Gly672fs Likely pathogenic ★ same condition
CNGA3 p.Lys465_Ile470del Pathogenic ★ same condition
CNGA3 p.Trp440fs Pathogenic ★ same condition
CNGA3 p.Val456fs Pathogenic ★ 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/cnga3-p-gln537fs (accessed [today's date]).

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