Is CACNA2D2 p.Arg736Cys (c.2206C>T) pathogenic?

CACNA2D2 p.Arg736Cys (c.2206C>T) is classified Uncertain significance in CACNA2D2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-05). AlphaMissense: ambiguous (0.4878); Very rare (popmax 8.49e-05%, nfe); Associated with early-infantile DEE.

What condition is associated with CACNA2D2 p.Arg736Cys (c.2206C>T)?

CACNA2D2 p.Arg736Cys (c.2206C>T) is associated with early-infantile DEE (ClinVar).

How common is CACNA2D2 p.Arg736Cys (c.2206C>T) in the general population?

CACNA2D2 p.Arg736Cys (c.2206C>T) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about CACNA2D2 p.Arg736Cys (c.2206C>T)?

AlphaMissense predicts ambiguous (score 0.4878) — an in-silico prediction, not a clinical call.

CACNA2D2 p.Arg736Cys

c.2206C>T · rs2109411511 · VCV1523008

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4878 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Conditions

early-infantile DEE

Computational evidence

Protein change
AlphaMissense	0.4878	ambiguous
REVEL	0.435	indeterminate
SaProt	LLR -10.46	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.75 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.4	GERP 2.2, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 137 kb · p 1.1e-21 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R743C vs ClinVar R736C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,177,174 alleles

Overall 6.86e-05% 1/1,457,522 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.Arg736Cys
Coding: c.2206C>T
MANE Select: NM_006030
dbSNP: rs2109411511
Type: single nucleotide variant
Location: chr3:50367840 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.48
Residue 736: a disulfide bond

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-arg736cys (accessed [today's date]).

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