Is CACNG2 p.Ala100Ser (c.298G>T) pathogenic?

CACNG2 p.Ala100Ser (c.298G>T) is classified Uncertain significance in CACNG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-14). AlphaMissense: ambiguous (0.5448); Very rare (popmax 8.47e-05%, nfe); Associated with intellectual disability, autosomal dominant 10.

What condition is associated with CACNG2 p.Ala100Ser (c.298G>T)?

CACNG2 p.Ala100Ser (c.298G>T) is associated with intellectual disability, autosomal dominant 10 (ClinVar).

How common is CACNG2 p.Ala100Ser (c.298G>T) in the general population?

CACNG2 p.Ala100Ser (c.298G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CACNG2 p.Ala100Ser (c.298G>T)?

AlphaMissense predicts ambiguous (score 0.5448) — an in-silico prediction, not a clinical call.

CACNG2 p.Ala100Ser

c.298G>T · rs1935129350 · VCV931257

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5448 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

intellectual disability, autosomal dominant 10

Computational evidence

Protein change
AlphaMissense	0.5448	ambiguous
REVEL	0.682	pathogenic-leaning
SaProt	LLR -8.99	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP -0.42, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 138 kb · p 8.6e-08 · regional, not allelic
Overall
CADD	23.5	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 8.47e-05% European (non-Finnish) · 1/1,180,020 alleles

Overall 6.84e-05% 1/1,461,712 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.Ala100Ser
Coding: c.298G>T
MANE Select: NM_006078
dbSNP: rs1935129350
Type: single nucleotide variant
Location: chr22:36566491 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.26 · 5 PDB

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

Disease context

intellectual disability, autosomal dominant 10 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CACNG2 p.Arg319Pro Uncertain significance ★★ ⚠ same condition
CACNG2 p.Glu126Lys Uncertain significance ★★ ⚠ same condition
CACNG2 p.Ala197Thr Uncertain significance ★ ⚠ same condition
CACNG2 p.Ile223Met Uncertain significance ★ ⚠ same condition
CACNG2 p.Ser148Asn Uncertain significance ★ same condition
CACNG2 p.Ser46Arg Uncertain significance ★ ⚠ same condition
CACNG2 p.Thr287Ser Uncertain significance ★ ⚠ same condition
CACNG2 p.Thr315Arg Uncertain significance ★ ⚠ 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/cacng2-p-ala100ser (accessed [today's date]).

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