Is CACNA2D3 p.Ser929Phe (c.2786C>T) pathogenic?

CACNA2D3 p.Ser929Phe (c.2786C>T) is classified Uncertain significance in CACNA2D3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-29). AlphaMissense: likely benign (0.167); Very rare (popmax 8.64e-05%, nfe).

How common is CACNA2D3 p.Ser929Phe (c.2786C>T) in the general population?

CACNA2D3 p.Ser929Phe (c.2786C>T) is very rare (popmax 8.64e-05%, nfe) (gnomAD).

What do computational predictors say about CACNA2D3 p.Ser929Phe (c.2786C>T)?

AlphaMissense predicts likely benign (score 0.167) — an in-silico prediction, not a clinical call.

CACNA2D3 p.Ser929Phe

c.2786C>T · rs1703128887 · VCV2610465

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.167 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.64e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.167	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -8.98	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.25 · evaluated, not missing
Pangolin	Δ0.22	loss · gain 0.06 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 504 kb · p 0.004 · regional, not allelic
Overall
CADD	24.2	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 8.64e-05% European (non-Finnish) · 1/1,157,232 alleles

Overall 7.09e-05% 1/1,411,064 alleles · very 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: CACNA2D3
Protein: p.Ser929Phe
Coding: c.2786C>T
MANE Select: NM_018398
dbSNP: rs1703128887
Type: single nucleotide variant
Location: chr3:55007809 (GRCh38)
Gene constraint: LOEUF 0.454 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.30
Residue 929: 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-ser929phe (accessed [today's date]).

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