Is CACNA2D2 p.Arg102Trp (c.304C>T) pathogenic?

CACNA2D2 p.Arg102Trp (c.304C>T) is classified Uncertain significance in CACNA2D2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-18). AlphaMissense: likely benign (0.1705); Ultra-rare (popmax 0.0869%, eas); Associated with Inborn genetic diseases.

What condition is associated with CACNA2D2 p.Arg102Trp (c.304C>T)?

CACNA2D2 p.Arg102Trp (c.304C>T) is associated with Inborn genetic diseases, developmental and epileptic encephalopathy (ClinVar).

How common is CACNA2D2 p.Arg102Trp (c.304C>T) in the general population?

CACNA2D2 p.Arg102Trp (c.304C>T) is ultra-rare (popmax 0.0869%, eas) (gnomAD).

What do computational predictors say about CACNA2D2 p.Arg102Trp (c.304C>T)?

AlphaMissense predicts likely benign (score 0.1705) — an in-silico prediction, not a clinical call.

CACNA2D2 p.Arg102Trp

c.304C>T · rs568540115 · VCV647638

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1705 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0869%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1705	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -8.24	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 3.8	GERP -0.082, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 137 kb · p 1.1e-21 · regional, not allelic
Overall
CADD	26.7	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 0.0869% East Asian · 39/44,882 alleles

Filtering AF 0.0653% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0578%

Overall 0.00359% 58/1,613,988 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0869%	1,151
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0064%	15,622
Admixed American	0.005%	20,008
South Asian	0.0022%	45,540
African / African-American	0.00133%	75,032
European (non-Finnish)	0.000678%	147,483

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.Arg102Trp
Coding: c.304C>T
MANE Select: NM_006030
dbSNP: rs568540115
Type: single nucleotide variant
Location: chr3:50434414 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy

Similar variants

CACNA2D2 p.Arg102= Likely benign ★★ same residue
CACNA2D2 p.Arg102Gln Uncertain significance ★ ⚠ same residue
CACNA2D2 c.842+6C>T Uncertain significance ★★ same condition
CACNA2D2 p.Ala1096Val Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Ala253Thr Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Ala582Val Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Ala753Thr Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Arg1039Lys 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-arg102trp (accessed [today's date]).

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