Is CACNA2D2 p.Arg75Trp (c.223C>T) pathogenic?

CACNA2D2 p.Arg75Trp (c.223C>T) is classified Uncertain significance in CACNA2D2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-12-02). AlphaMissense: likely benign (0.1546); Rare (popmax 0.182%, mid); Associated with cerebellar atrophy with seizures and variable developmental delay.

How common is CACNA2D2 p.Arg75Trp (c.223C>T) in the general population?

CACNA2D2 p.Arg75Trp (c.223C>T) is rare (popmax 0.182%, mid) (gnomAD).

What do computational predictors say about CACNA2D2 p.Arg75Trp (c.223C>T)?

AlphaMissense predicts likely benign (score 0.1546) — an in-silico prediction, not a clinical call.

CACNA2D2 p.Arg75Trp

Q: What condition is associated with CACNA2D2 p.Arg75Trp (c.223C>T)?

CACNA2D2 p.Arg75Trp (c.223C>T) is associated with cerebellar atrophy with seizures and variable developmental delay, developmental and epileptic encephalopathy (ClinVar).

c.223C>T · rs372777713 · VCV863596

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1546 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.182%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebellar atrophy with seizures and variable developmental delay

Computational evidence

Protein change
AlphaMissense	0.1546	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -8.45	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 5.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 137 kb · p 1.1e-21 · regional, not allelic
Overall
CADD	28.8	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 0.182% Middle Eastern · 11/6,034 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.079%

Overall 0.0102% 162/1,593,950 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.182%	549
Remaining individualsnot grpmax-eligible	0.0162%	6,175
European (non-Finnish)	0.0116%	8,611
African / African-American	0.00268%	37,353
East Asian	0.00227%	44,040
South Asian	0.00227%	44,073

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: CACNA2D2
Protein: p.Arg75Trp
Coding: c.223C>T
MANE Select: NM_006030
dbSNP: rs372777713
Type: single nucleotide variant
Location: chr3:50476183 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.48

Full CACNA2D2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cerebellar atrophy with seizures and variable developmental delay — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy

Similar variants

CACNA2D2 p.Arg75Gln Benign ★★ same residue
CACNA2D2 p.Gln519Ter Pathogenic/Likely pathogenic ★★ same condition
CACNA2D2 c.1907+3A>C Uncertain significance ★★ same condition
CACNA2D2 c.785-3C>T Uncertain significance ★★ same condition
CACNA2D2 c.842+6C>T Uncertain significance ★★ same condition
CACNA2D2 p.Ala1096Val Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Ala582Val Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Ala753Thr 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/cacna2d2-p-arg75trp (accessed [today's date]).

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