Is CACNA2D2 p.Pro999Ser (c.2995C>T) pathogenic?

CACNA2D2 p.Pro999Ser (c.2995C>T) is classified Conflicting classifications of pathogenicity in CACNA2D2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0615); Rare (popmax 0.177%, sas); Associated with early-infantile DEE.

What condition is associated with CACNA2D2 p.Pro999Ser (c.2995C>T)?

CACNA2D2 p.Pro999Ser (c.2995C>T) is associated with early-infantile DEE, developmental and epileptic encephalopathy (ClinVar).

How common is CACNA2D2 p.Pro999Ser (c.2995C>T) in the general population?

CACNA2D2 p.Pro999Ser (c.2995C>T) is rare (popmax 0.177%, sas) (gnomAD).

What do computational predictors say about CACNA2D2 p.Pro999Ser (c.2995C>T)?

AlphaMissense predicts likely benign (score 0.0615) — an in-silico prediction, not a clinical call.

CACNA2D2 p.Pro999Ser

c.2995C>T · rs146587089 · VCV411005

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0615 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.177%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

early-infantile DEE

Computational evidence

Protein change
AlphaMissense	0.0615	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -5.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP -1.6, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,380 bp · p 0.33 · regional, not allelic
Overall
CADD	19.21	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 P1006S vs ClinVar P999S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.177% South Asian · 161/91,070 alleles

Filtering AF 0.154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.146%

Overall 0.138% 2,227/1,613,428 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.177%	566
Remaining individualsnot grpmax-eligible	0.176%	568
European (non-Finnish)	0.154%	648
Admixed American	0.142%	706
Finnishnot grpmax-eligible	0.0472%	2,119
African / African-American	0.024%	4,169
Middle Eastern	0.0165%	6,058
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,590

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.Pro999Ser
Coding: c.2995C>T
MANE Select: NM_006030
dbSNP: rs146587089
Type: single nucleotide variant
Location: chr3:50365459 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.48
Residue 999: 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

Also linked: developmental and epileptic encephalopathy

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 c.842+6C>T Uncertain significance ★★ same condition
CACNA2D2 p.Ala1096Thr Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Ala1096Val Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Ala253Thr 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-pro999ser (accessed [today's date]).

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