Is CACNA2D2 p.Arg784His (c.2351G>A) pathogenic?

CACNA2D2 p.Arg784His (c.2351G>A) is classified Uncertain significance in CACNA2D2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-24). AlphaMissense: likely benign (0.2194); Very rare (popmax 0.00446%, eas); Associated with early-infantile DEE.

What condition is associated with CACNA2D2 p.Arg784His (c.2351G>A)?

CACNA2D2 p.Arg784His (c.2351G>A) is associated with early-infantile DEE (ClinVar).

How common is CACNA2D2 p.Arg784His (c.2351G>A) in the general population?

CACNA2D2 p.Arg784His (c.2351G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CACNA2D2 p.Arg784His (c.2351G>A)?

AlphaMissense predicts likely benign (score 0.2194) — an in-silico prediction, not a clinical call.

CACNA2D2 p.Arg784His

c.2351G>A · rs779297579 · VCV949656

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2194 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

early-infantile DEE

Computational evidence

Protein change
AlphaMissense	0.2194	likely benign
REVEL	0.71	pathogenic-leaning
SaProt	LLR -8.44	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.41 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP -0.62, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 137 kb · p 1.1e-21 · regional, not allelic
Overall
CADD	29.3	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 R791H vs ClinVar R784H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,890 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000558% 9/1,613,798 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,445
South Asian	0.0022%	45,544
Remaining individualsnot grpmax-eligible	0.0016%	62,476
Finnishnot grpmax-eligible	0.00157%	63,806
African / African-American	0.00134%	74,902
European (non-Finnish)	0.000169%	590,012

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.Arg784His
Coding: c.2351G>A
MANE Select: NM_006030
dbSNP: rs779297579
Type: single nucleotide variant
Location: chr3:50367444 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.48
Residue 784: 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 p.Arg784= Likely benign ★ 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
CACNA2D2 p.Ala1096Thr Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Ala253Thr Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Arg188Ser 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-arg784his (accessed [today's date]).

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