Is CACNA2D2 p.Arg6Trp (c.16C>T) pathogenic?

CACNA2D2 p.Arg6Trp (c.16C>T) is classified Uncertain significance in CACNA2D2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-03). AlphaMissense: ambiguous (0.3718); Ultra-rare (popmax 0.0107%, eas); Associated with developmental and epileptic encephalopathy.

What condition is associated with CACNA2D2 p.Arg6Trp (c.16C>T)?

CACNA2D2 p.Arg6Trp (c.16C>T) is associated with developmental and epileptic encephalopathy (ClinVar).

How common is CACNA2D2 p.Arg6Trp (c.16C>T) in the general population?

CACNA2D2 p.Arg6Trp (c.16C>T) is ultra-rare (popmax 0.0107%, eas) (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.Arg6Trp (c.16C>T)?

AlphaMissense predicts ambiguous (score 0.3718) — an in-silico prediction, not a clinical call.

CACNA2D2 p.Arg6Trp

c.16C>T · rs1217312363 · VCV2077338

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3718 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

developmental and epileptic encephalopathy

Computational evidence

Protein change
AlphaMissense	0.3718	ambiguous
REVEL	0.054	moderately benign-leaning
SaProt	LLR -8.38	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP -1.1, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 137 kb · p 1.1e-21 · regional, not allelic
Overall
CADD	23.4	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 0.0107% East Asian · 1/9,324 alleles

Overall 0.000674% 1/148,280 alleles · ultra-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.Arg6Trp
Coding: c.16C>T
MANE Select: NM_006030
dbSNP: rs1217312363
Type: single nucleotide variant
Location: chr3:50503408 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.48
Residue 6: the 'disordered' region

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 p.Arg6Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-arg6trp (accessed [today's date]).

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