Is CACNA2D2 p.Pro261= (c.783G>A) pathogenic?

CACNA2D2 p.Pro261= (c.783G>A) is classified Conflicting classifications of pathogenicity in CACNA2D2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-03-21). Ultra-rare (popmax 0.0165%, mid); Associated with developmental and epileptic encephalopathy.

What condition is associated with CACNA2D2 p.Pro261= (c.783G>A)?

CACNA2D2 p.Pro261= (c.783G>A) is associated with developmental and epileptic encephalopathy (ClinVar).

How common is CACNA2D2 p.Pro261= (c.783G>A) in the general population?

CACNA2D2 p.Pro261= (c.783G>A) is ultra-rare (popmax 0.0165%, mid) (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.

CACNA2D2 p.Pro261=

c.783G>A · rs370672130 · VCV947898

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

developmental and epileptic encephalopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2	GERP -3.9
Overall
CADD	9.508	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,074 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.00304% 49/1,613,594 alleles · ultra-rare exomes 48/1,461,496 · genomes 1/152,098 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,074
Ashkenazi Jewishnot grpmax-eligible	0.00677%	14,781
Remaining individualsnot grpmax-eligible	0.0048%	20,817
African / African-American	0.00401%	24,963
European (non-Finnish)	0.00322%	31,046
Admixed American	0.00167%	59,982
Finnishnot grpmax-eligible	0.00156%	64,018

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.Pro261=
Coding: c.783G>A
MANE Select: NM_006030
dbSNP: rs370672130
Type: single nucleotide variant
Location: chr3:50380996 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.48
Residue 261: a UniProt-annotated variant site (in casvdd; uncertain significance)

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.Pro261Leu Uncertain significance ★★ ⚠ 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-pro261 (accessed [today's date]).

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