Is CACNA2D2 p.Pro43= (c.129G>A) pathogenic?

CACNA2D2 p.Pro43= (c.129G>A) is classified Likely benign in CACNA2D2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-13). Very rare (popmax 0.00503%, afr); Associated with early-infantile DEE.

What condition is associated with CACNA2D2 p.Pro43= (c.129G>A)?

CACNA2D2 p.Pro43= (c.129G>A) is associated with early-infantile DEE (ClinVar).

How common is CACNA2D2 p.Pro43= (c.129G>A) in the general population?

CACNA2D2 p.Pro43= (c.129G>A) is very rare (popmax 0.00503%, afr) (gnomAD).

CACNA2D2 p.Pro43=

c.129G>A · rs983143827 · VCV1605837

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00503%, afr)

Conditions

early-infantile DEE

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.91	GERP -2.1, phastCons 0.93
Overall
CADD	9.242	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00503% African / African-American · 3/59,684 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00067%

Overall 0.000379% 4/1,055,236 alleles · very rare exomes 1/904,354 · genomes 3/150,882 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00503%	19,895
European (non-Finnish)	0.000119%	839,870

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.Pro43=
Coding: c.129G>A
MANE Select: NM_006030
dbSNP: rs983143827
Type: single nucleotide variant
Location: chr3:50503295 (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

early-infantile DEE — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CACNA2D2 c.2234+1G>A Likely pathogenic ★★ same condition
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 p.Ala1096Thr Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Ala253Thr Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Arg188Ser Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Arg422Cys 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-pro43 (accessed [today's date]).

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