Is CACNG2 p.Ser228Thr (c.683G>C) pathogenic?

CACNG2 p.Ser228Thr (c.683G>C) is classified Uncertain significance in CACNG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-31). AlphaMissense: likely benign (0.2006); Very rare (popmax 0.00167%, amr).

How common is CACNG2 p.Ser228Thr (c.683G>C) in the general population?

CACNG2 p.Ser228Thr (c.683G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CACNG2 p.Ser228Thr (c.683G>C)?

AlphaMissense predicts likely benign (score 0.2006) — an in-silico prediction, not a clinical call.

CACNG2 p.Ser228Thr

c.683G>C · rs1250674878 · VCV2561302

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2006 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2006	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -9.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.82, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 371 bp · p 0.65 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,994 alleles

Overall 0.000657% 1/152,154 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: CACNG2
Protein: p.Ser228Thr
Coding: c.683G>C
MANE Select: NM_006078
dbSNP: rs1250674878
Type: single nucleotide variant
Location: chr22:36564640 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.26 · 5 PDB
Residue 228: a β-strand

Full CACNG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CACNG2 p.Ala100Ser Uncertain significance ★★ ⚠ same type
CACNG2 p.Ala214Thr Uncertain significance ★★ ⚠ same type
CACNG2 p.Arg319Pro Uncertain significance ★★ ⚠ same type
CACNG2 p.Gln298Arg Uncertain significance ★★ ⚠ same type
CACNG2 p.Glu126Lys Uncertain significance ★★ ⚠ same type
CACNG2 c.212-12C>A Likely benign ★★ same type
CACNG2 p.Val193= Likely benign ★★ same type
CACNG2 c.436+1G>A Uncertain significance ★ 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/cacng2-p-ser228thr (accessed [today's date]).

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