Is CACNA2D2 p.Val201Ile (c.601G>A) pathogenic?

CACNA2D2 p.Val201Ile (c.601G>A) is classified Uncertain significance in CACNA2D2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-10-25). AlphaMissense: likely benign (0.1207); Very rare (popmax 8.47e-05%, nfe); Associated with early-infantile DEE.

What condition is associated with CACNA2D2 p.Val201Ile (c.601G>A)?

CACNA2D2 p.Val201Ile (c.601G>A) is associated with early-infantile DEE (ClinVar).

How common is CACNA2D2 p.Val201Ile (c.601G>A) in the general population?

CACNA2D2 p.Val201Ile (c.601G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CACNA2D2 p.Val201Ile (c.601G>A)?

AlphaMissense predicts likely benign (score 0.1207) — an in-silico prediction, not a clinical call.

CACNA2D2 p.Val201Ile

c.601G>A · rs866928902 · VCV1042337

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1207 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

early-infantile DEE

Computational evidence

Protein change
AlphaMissense	0.1207	likely benign
REVEL	0.215	benign-leaning
SaProt	LLR -11.41	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 137 kb · p 1.1e-21 · regional, not allelic
Overall
CADD	24.8	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 8.47e-05% European (non-Finnish) · 1/1,180,024 alleles

Overall 0.000657% 1/152,214 alleles · very 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.Val201Ile
Coding: c.601G>A
MANE Select: NM_006030
dbSNP: rs866928902
Type: single nucleotide variant
Location: chr3:50384247 (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-val201ile (accessed [today's date]).

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