Is CACNA2D2 p.Pro40= (c.120C>T) pathogenic?

CACNA2D2 p.Pro40= (c.120C>T) is classified Likely benign in CACNA2D2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-05). Ultra-rare (popmax 0.0132%, nfe); Associated with early-infantile DEE.

What condition is associated with CACNA2D2 p.Pro40= (c.120C>T)?

CACNA2D2 p.Pro40= (c.120C>T) is associated with early-infantile DEE (ClinVar).

How common is CACNA2D2 p.Pro40= (c.120C>T) in the general population?

CACNA2D2 p.Pro40= (c.120C>T) is ultra-rare (popmax 0.0132%, nfe) (gnomAD).

CACNA2D2 p.Pro40=

c.120C>T · rs907775113 · VCV530582

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, nfe)

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 0.71	GERP 0.5, phastCons 0.93
Overall
CADD	9.905	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0132% European (non-Finnish) · 93/703,376 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.0103% 93/904,544 alleles · ultra-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: CACNA2D2
Protein: p.Pro40=
Coding: c.120C>T
MANE Select: NM_006030
dbSNP: rs907775113
Type: single nucleotide variant
Location: chr3:50503304 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.48
Residue 40: the 'disordered' region

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 p.Pro40Arg Uncertain significance ★ ⚠ same residue
CACNA2D2 p.Pro40His Uncertain significance ★ ⚠ same residue
CACNA2D2 p.Pro40Leu Uncertain significance ★ ⚠ same residue
CACNA2D2 p.Pro40Ser Uncertain significance ★★ ⚠ same residue
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

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-pro40 (accessed [today's date]).

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