Is CACNA2D3 p.Pro1071Arg (c.3212C>G) pathogenic?

CACNA2D3 p.Pro1071Arg (c.3212C>G) is classified Uncertain significance in CACNA2D3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-22). AlphaMissense: likely benign (0.068); Ultra-rare (popmax 0.034%, sas).

How common is CACNA2D3 p.Pro1071Arg (c.3212C>G) in the general population?

CACNA2D3 p.Pro1071Arg (c.3212C>G) is ultra-rare (popmax 0.034%, sas) (gnomAD).

What do computational predictors say about CACNA2D3 p.Pro1071Arg (c.3212C>G)?

AlphaMissense predicts likely benign (score 0.068) — an in-silico prediction, not a clinical call.

CACNA2D3 p.Pro1071Arg

c.3212C>G · VCV3826712

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.068 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.034%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.068	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -6.73	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 -0.89	GERP -4.3
Regional constraint	o/e 0.91	unconstrained · MANE · 504 kb · p 0.004 · regional, not allelic
Overall
CADD	0.151	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 0.034% South Asian · 31/91,078 alleles

Filtering AF 0.0246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00465% 75/1,613,670 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.034%	2,938
Middle Eastern	0.0329%	3,041
Remaining individualsnot grpmax-eligible	0.0048%	20,818
European (non-Finnish)	0.00322%	31,048
East Asian	0.00223%	44,878

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: CACNA2D3
Protein: p.Pro1071Arg
Coding: c.3212C>G
MANE Select: NM_018398
Type: single nucleotide variant
Location: chr3:55074142 (GRCh38)
Gene constraint: LOEUF 0.454 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.30

Full CACNA2D3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CACNA2D3 p.Pro1071Leu Uncertain significance ★ ⚠ same residue
CACNA2D3 c.676+9A>C Benign ★★ same type
CACNA2D3 p.Ala1064= Benign ★★ same type
LRTM1 p.Glu265Gln Benign ★★ same type
LRTM1 p.Val294Ile Benign ★★ same type
CACNA2D3 c.2620-4A>G Uncertain significance ★ same type
CACNA2D3 p.Ala1070Thr Uncertain significance ★ ⚠ same type
CACNA2D3 p.Ala14Thr 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/cacna2d3-p-pro1071arg (accessed [today's date]).

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