Is CNGA1 p.Ser563Arg (c.1689T>G) pathogenic?

CNGA1 p.Ser563Arg (c.1689T>G) is classified Uncertain significance in CNGA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-13). AlphaMissense: likely pathogenic (0.9998); Very rare (popmax 0.00333%, amr).

How common is CNGA1 p.Ser563Arg (c.1689T>G) in the general population?

CNGA1 p.Ser563Arg (c.1689T>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CNGA1 p.Ser563Arg (c.1689T>G)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

CNGA1 p.Ser563Arg

c.1689T>G · rs1346695256 · VCV1929980

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic · top 2% in CNGA1
REVEL	0.901	moderately pathogenic-leaning
SaProt	LLR -17.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.68	GERP -3.7, phastCons 0.98
Regional constraint	o/e 0.91	unconstrained · MANE · 16 kb · p 0.011 · regional, not allelic
Overall
CADD	21.2	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 S567R vs ClinVar S563R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,998 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,614,046 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: CNGA1
Protein: p.Ser563Arg
Coding: c.1689T>G
MANE Select: NM_001379270
dbSNP: rs1346695256
Type: single nucleotide variant
Location: chr4:47936793 (GRCh38)
Gene constraint: LOEUF 0.779 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.88 · 19 PDB
Residue 563: the 'cyclic nucleotide-binding domain' region; a β-strand

Full CNGA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNGA1 p.Ser563Gly Uncertain significance ★ ⚠ same residue
CNGA1 p.Ser563Ile Uncertain significance ★ ⚠ same residue
CNGA1 p.Ser563fs Likely pathogenic ★ same residue
CNGA1 c.107+1G>A Likely pathogenic ★★ same type
CNGA1 c.107+2T>G Likely pathogenic ★★ same type
CNGA1 c.545+2T>A Likely pathogenic ★★ same type
CNGA1 c.545+2T>C Likely pathogenic ★★ same type
CNGA1 c.546-1G>C 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/cnga1-p-ser563arg (accessed [today's date]).

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