Is CACNA2D1 p.Ile150Val (c.448A>G) pathogenic?

CACNA2D1 p.Ile150Val (c.448A>G) is classified Uncertain significance in CACNA2D1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-18). AlphaMissense: likely benign (0.0597); Ultra-rare (popmax 0.0165%, mid).

How common is CACNA2D1 p.Ile150Val (c.448A>G) in the general population?

CACNA2D1 p.Ile150Val (c.448A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CACNA2D1 p.Ile150Val (c.448A>G)?

AlphaMissense predicts likely benign (score 0.0597) — an in-silico prediction, not a clinical call.

CACNA2D1 p.Ile150Val

c.448A>G · VCV3379767

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0597 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0597	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -5.74	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 0.81	GERP -2.5, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 379 kb · p 1.9e-06 · regional, not allelic
Overall
CADD	2.941	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Overall 6.84e-05% 1/1,461,608 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: CACNA2D1
Protein: p.Ile150Val
Coding: c.448A>G
MANE Select: NM_000722
Type: single nucleotide variant
Location: chr7:82117122 (GRCh38)
Gene constraint: LOEUF 0.437 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.97 · 30 PDB
Residue 150: a β-strand

Full CACNA2D1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CACNA2D1 p.Ile150Thr Uncertain significance ★ ⚠ same residue
CACNA2D1 c.1662+3G>A Uncertain significance ★★ same type
CACNA2D1 c.2574+3A>G Uncertain significance ★★ same type
CACNA2D1 c.3160-1G>A Uncertain significance ★★ same type
CACNA2D1 p.Ala1022Glu Uncertain significance ★★ ⚠ same type
CACNA2D1 p.Ala104Thr Uncertain significance ★★ ⚠ same type
CACNA2D1 p.Ala104Val Uncertain significance ★★ ⚠ same type
CACNA2D1 p.Ala30Pro Uncertain significance ★★ ⚠ same type

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/cacna2d1-p-ile150val (accessed [today's date]).

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