Is CNGA3 p.Phe249Ser (c.746T>C) pathogenic?

CNGA3 p.Phe249Ser (c.746T>C) is classified Pathogenic in CNGA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-25). AlphaMissense: likely pathogenic (0.7386); Very rare (popmax 0.000169%, nfe).

How common is CNGA3 p.Phe249Ser (c.746T>C) in the general population?

CNGA3 p.Phe249Ser (c.746T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CNGA3 p.Phe249Ser (c.746T>C)?

AlphaMissense predicts likely pathogenic (score 0.7386) — an in-silico prediction, not a clinical call.

CNGA3 p.Phe249Ser

c.746T>C · rs2467027461 · VCV2203118

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7386 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7386	likely pathogenic ✓ concordant with ClinVar
REVEL	0.934	strongly pathogenic-leaning
SaProt	LLR -10.23	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 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 1,336 bp · p 0.34 · regional, not allelic
Overall
CADD	25.7	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 0.000169% European (non-Finnish) · 2/1,180,038 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,894 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.Phe249Ser
Coding: c.746T>C
MANE Select: NM_001298
dbSNP: rs2467027461
Type: single nucleotide variant
Location: chr2:98395916 (GRCh38)
Gene constraint: LOEUF 1.126 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.33 · 10 PDB
Residue 249: an α-helix; a UniProt-annotated variant site (in achm2)

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

Similar variants

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
CNGA3 p.Arg129Ter Pathogenic ★★ same type
CNGA3 p.Arg221Ter 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-phe249ser (accessed [today's date]).

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