Is CACNA2D2 p.Pro40His (c.119C>A) pathogenic?

CACNA2D2 p.Pro40His (c.119C>A) is classified Uncertain significance in CACNA2D2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-01). AlphaMissense: likely benign (0.0882); Absent from gnomAD v4.1; Associated with early-infantile DEE.

What condition is associated with CACNA2D2 p.Pro40His (c.119C>A)?

CACNA2D2 p.Pro40His (c.119C>A) is associated with early-infantile DEE (ClinVar).

How common is CACNA2D2 p.Pro40His (c.119C>A) in the general population?

CACNA2D2 p.Pro40His (c.119C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CACNA2D2 p.Pro40His (c.119C>A)?

AlphaMissense predicts likely benign (score 0.0882) — an in-silico prediction, not a clinical call.

CACNA2D2 p.Pro40His

c.119C>A · rs1575798996 · VCV1011885

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0882 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 892,150)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

early-infantile DEE

Computational evidence

Protein change
AlphaMissense	0.0882	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -9.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Regional constraint	o/e 0.72	unconstrained · MANE · 137 kb · p 1.1e-21 · regional, not allelic
Overall
CADD	20.4	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

No allele count reported in gnomAD v4.1 (AN 892,150). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CACNA2D2
Protein: p.Pro40His
Coding: c.119C>A
MANE Select: NM_006030
dbSNP: rs1575798996
Type: single nucleotide variant
Location: chr3:50503305 (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.Pro40= Likely benign ★★ same residue
CACNA2D2 p.Pro40Arg 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-pro40his (accessed [today's date]).

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