Is CACNA2D2 p.Arg6Pro (c.17G>C) pathogenic?

CACNA2D2 p.Arg6Pro (c.17G>C) is classified Conflicting classifications of pathogenicity in CACNA2D2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-16). AlphaMissense: likely benign (0.0911); Ultra-rare (popmax 0.0597%, afr); Associated with cerebellar atrophy with seizures and variable developmental delay.

How common is CACNA2D2 p.Arg6Pro (c.17G>C) in the general population?

CACNA2D2 p.Arg6Pro (c.17G>C) is ultra-rare (popmax 0.0597%, afr) (gnomAD).

What do computational predictors say about CACNA2D2 p.Arg6Pro (c.17G>C)?

AlphaMissense predicts likely benign (score 0.0911) — an in-silico prediction, not a clinical call.

CACNA2D2 p.Arg6Pro

Q: What condition is associated with CACNA2D2 p.Arg6Pro (c.17G>C)?

CACNA2D2 p.Arg6Pro (c.17G>C) is associated with cerebellar atrophy with seizures and variable developmental delay, developmental and epileptic encephalopathy (ClinVar).

c.17G>C · rs1317078806 · VCV461303

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0911 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0597%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebellar atrophy with seizures and variable developmental delay

Computational evidence

Protein change
AlphaMissense	0.0911	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -6.24	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 1.6	GERP -2.3, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 137 kb · p 1.1e-21 · regional, not allelic
Overall
CADD	21.6	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 0.0597% African / African-American · 25/41,910 alleles

Filtering AF 0.0415% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0354%

Overall 0.0137% 30/218,334 alleles · ultra-rare exomes 0/71,468 · genomes 30/146,866 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0597%	1,676
East Asian	0.0437%	2,286
Admixed American	0.00585%	17,084

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.Arg6Pro
Coding: c.17G>C
MANE Select: NM_006030
dbSNP: rs1317078806
Type: single nucleotide variant
Location: chr3:50503407 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.48
Residue 6: the 'disordered' region

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.Arg6Trp Uncertain significance ★ ⚠ 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-arg6pro (accessed [today's date]).

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