Is CACNA2D2 p.Arg950Trp (c.2848C>T) pathogenic?

CACNA2D2 p.Arg950Trp (c.2848C>T) is classified Uncertain significance in CACNA2D2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-26). AlphaMissense: ambiguous (0.4786); Very rare (popmax 0.00534%, afr); Associated with developmental and epileptic encephalopathy.

What condition is associated with CACNA2D2 p.Arg950Trp (c.2848C>T)?

CACNA2D2 p.Arg950Trp (c.2848C>T) is associated with developmental and epileptic encephalopathy (ClinVar).

How common is CACNA2D2 p.Arg950Trp (c.2848C>T) in the general population?

CACNA2D2 p.Arg950Trp (c.2848C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

How is Non-specific syndromic intellectual disability inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CACNA2D2 p.Arg950Trp (c.2848C>T)?

AlphaMissense predicts ambiguous (score 0.4786) — an in-silico prediction, not a clinical call.

CACNA2D2 p.Arg950Trp

c.2848C>T · rs1209696501 · VCV642435

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4786 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

developmental and epileptic encephalopathy

Computational evidence

Protein change
AlphaMissense	0.4786	ambiguous
REVEL	0.657	pathogenic-leaning
SaProt	LLR -7.44	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP -1.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,380 bp · p 0.33 · regional, not allelic
Overall
CADD	27.2	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 R957W vs ClinVar R950W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,912 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000372% 6/1,612,752 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,728
Remaining individualsnot grpmax-eligible	0.0016%	62,446
European (non-Finnish)	8.48e-05%	1,179,690

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.Arg950Trp
Coding: c.2848C>T
MANE Select: NM_006030
dbSNP: rs1209696501
Type: single nucleotide variant
Location: chr3:50366025 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.48
Residue 950: a disulfide bond

Full CACNA2D2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Non-specific syndromic intellectual disability (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Childhood, Infancy

Similar variants

CACNA2D2 c.842+6C>T Uncertain significance ★★ same condition
CACNA2D2 p.Ala1096Val Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Ala582Val Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Ala753Thr Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Arg102Trp Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Arg1039Lys Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Arg149Cys Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Arg149His 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-arg950trp (accessed [today's date]).

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