Is CACNA2D3 p.Arg8Ser (c.22C>A) pathogenic?

CACNA2D3 p.Arg8Ser (c.22C>A) is classified Uncertain significance in CACNA2D3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-03). AlphaMissense: likely benign (0.2066); Very rare (popmax 0.00878%, amr).

How common is CACNA2D3 p.Arg8Ser (c.22C>A) in the general population?

CACNA2D3 p.Arg8Ser (c.22C>A) is very rare (popmax 0.00878%, amr) (gnomAD).

What do computational predictors say about CACNA2D3 p.Arg8Ser (c.22C>A)?

AlphaMissense predicts likely benign (score 0.2066) — an in-silico prediction, not a clinical call.

CACNA2D3 p.Arg8Ser

c.22C>A · VCV3994555

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2066 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00878%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2066	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -7.49	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 0.42	GERP -1.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 264 kb · p 0.9 · regional, not allelic
Overall
CADD	16.21	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 0.00878% Admixed American · 2/22,792 alleles

Filtering AF 0.00691% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00638%

Overall 0.00726% 88/1,212,224 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00878%	11,396
European (non-Finnish)	0.00842%	11,882
Remaining individualsnot grpmax-eligible	0.0068%	14,717
Finnishnot grpmax-eligible	0.00305%	32,788

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.Arg8Ser
Coding: c.22C>A
MANE Select: NM_018398
Type: single nucleotide variant
Location: chr3:54122735 (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 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
CACNA2D3 p.Ala217Gly 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-arg8ser (accessed [today's date]).

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