Is CACNA2D2 p.Val817Ile (c.2449G>A) pathogenic?

CACNA2D2 p.Val817Ile (c.2449G>A) is classified Uncertain significance in CACNA2D2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-20). AlphaMissense: likely benign (0.1267); Very rare (popmax 0.00133%, afr); Associated with developmental and epileptic encephalopathy.

What condition is associated with CACNA2D2 p.Val817Ile (c.2449G>A)?

CACNA2D2 p.Val817Ile (c.2449G>A) is associated with developmental and epileptic encephalopathy (ClinVar).

How common is CACNA2D2 p.Val817Ile (c.2449G>A) in the general population?

CACNA2D2 p.Val817Ile (c.2449G>A) is very rare (popmax 0.00133%, 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.Val817Ile (c.2449G>A)?

AlphaMissense predicts likely benign (score 0.1267) — an in-silico prediction, not a clinical call.

CACNA2D2 p.Val817Ile

c.2449G>A · rs1346736959 · VCV655011

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1267 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

developmental and epileptic encephalopathy

Computational evidence

Protein change
AlphaMissense	0.1267	likely benign
REVEL	0.417	indeterminate
SaProt	LLR -9.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.4, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 137 kb · p 1.1e-21 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V824I vs ClinVar V817I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,048 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000753% 11/1,461,434 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,048
European (non-Finnish)	0.000847%	118,002

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.Val817Ile
Coding: c.2449G>A
MANE Select: NM_006030
dbSNP: rs1346736959
Type: single nucleotide variant
Location: chr3:50367062 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.48
Residue 817: 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-val817ile (accessed [today's date]).

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