Is CACNA2D3 p.Ser648Phe (c.1943C>T) pathogenic?

CACNA2D3 p.Ser648Phe (c.1943C>T) is classified Uncertain significance in CACNA2D3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-08). AlphaMissense: likely benign (0.1441); Very rare (popmax 0.00167%, amr).

How common is CACNA2D3 p.Ser648Phe (c.1943C>T) in the general population?

CACNA2D3 p.Ser648Phe (c.1943C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CACNA2D3 p.Ser648Phe (c.1943C>T)?

AlphaMissense predicts likely benign (score 0.1441) — an in-silico prediction, not a clinical call.

CACNA2D3 p.Ser648Phe

c.1943C>T · VCV3994566

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1441 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1441	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -5.47	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 6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 504 kb · p 0.004 · regional, not allelic
Overall
CADD	24.9	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 0.00167% Admixed American · 1/60,004 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000753% 11/1,461,638 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,004
European (non-Finnish)	0.000848%	117,984

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.Ser648Phe
Coding: c.1943C>T
MANE Select: NM_018398
Type: single nucleotide variant
Location: chr3:54885311 (GRCh38)
Gene constraint: LOEUF 0.454 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.30
Residue 648: a disulfide bond

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-ser648phe (accessed [today's date]).

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