Is CACNA2D2 p.Val91Ile (c.271G>A) pathogenic?

CACNA2D2 p.Val91Ile (c.271G>A) is classified Benign in CACNA2D2 (ClinVar, Single submitter, 2 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0857); Rare (popmax 0.644%, afr); Associated with early-infantile DEE.

What condition is associated with CACNA2D2 p.Val91Ile (c.271G>A)?

CACNA2D2 p.Val91Ile (c.271G>A) is associated with early-infantile DEE (ClinVar).

How common is CACNA2D2 p.Val91Ile (c.271G>A) in the general population?

CACNA2D2 p.Val91Ile (c.271G>A) is rare (popmax 0.644%, afr) (gnomAD).

What do computational predictors say about CACNA2D2 p.Val91Ile (c.271G>A)?

AlphaMissense predicts likely benign (score 0.0857) — an in-silico prediction, not a clinical call.

CACNA2D2 p.Val91Ile

c.271G>A · rs150190044 · VCV416550

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0857 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.644%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

early-infantile DEE

Computational evidence

Protein change
AlphaMissense	0.0857	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -6.82	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 4.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 137 kb · p 1.1e-21 · regional, not allelic
Overall
CADD	21.2	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 0.644% African / African-American · 482/74,858 alleles

Filtering AF 0.596% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.578%

Overall 0.0357% 572/1,602,268 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.644%	155
Admixed American	0.0761%	1,314
Remaining individualsnot grpmax-eligible	0.0467%	2,141
South Asian	0.00225%	44,450
East Asian	0.00225%	44,480
European (non-Finnish)	0.00111%	90,376

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.Val91Ile
Coding: c.271G>A
MANE Select: NM_006030
dbSNP: rs150190044
Type: single nucleotide variant
Location: chr3:50476135 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.48

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

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 p.Ala1096Thr Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Ala253Thr Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Arg188Ser Uncertain significance ★★ ⚠ same condition
CACNA2D2 p.Arg422Cys 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-val91ile (accessed [today's date]).

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