Is CACNA1E p.Thr2012Arg (c.6035C>G) pathogenic?

CACNA1E p.Thr2012Arg (c.6035C>G) is classified Likely benign in CACNA1E (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-11). AlphaMissense: likely benign (0.1742); Ultra-rare (popmax 0.0201%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CACNA1E p.Thr2012Arg (c.6035C>G)?

CACNA1E p.Thr2012Arg (c.6035C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CACNA1E p.Thr2012Arg (c.6035C>G) in the general population?

CACNA1E p.Thr2012Arg (c.6035C>G) is ultra-rare (popmax 0.0201%, nfe) (gnomAD).

What do computational predictors say about CACNA1E p.Thr2012Arg (c.6035C>G)?

AlphaMissense predicts likely benign (score 0.1742) — an in-silico prediction, not a clinical call.

CACNA1E p.Thr2012Arg

c.6035C>G · rs376772306 · VCV1362647

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1742 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1742	likely benign
REVEL	0.482	indeterminate
SaProt	LLR -6.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 13 kb · p 0.062 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0201% European (non-Finnish) · 237/1,177,752 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.0153% 246/1,609,720 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0201%	4,969
African / African-American	0.00669%	14,944
Remaining individualsnot grpmax-eligible	0.00642%	15,564

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: CACNA1E
Protein: p.Thr2012Arg
Coding: c.6035C>G
MANE Select: NM_001205293
dbSNP: rs376772306
Type: single nucleotide variant
Location: chr1:181794871 (GRCh38)
Gene constraint: LOEUF 0.221 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 60.56 · 5 PDB
Residue 2012: a UniProt-annotated variant site (in dee69; uncertain significance); the 'disordered' region

Full CACNA1E gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CACNA1E p.Gly352Arg Pathogenic/Likely pathogenic ★★ same condition
CACNA1E p.Ala487Ser Uncertain significance ★★ ⚠ same condition
CACNA1E p.Ala740Val Uncertain significance ★★ ⚠ same condition
CACNA1E p.Arg2059Trp Uncertain significance ★★ ⚠ same condition
CACNA1E p.Arg2154Ser Uncertain significance ★★ ⚠ same condition
CACNA1E p.Arg2156Cys Uncertain significance ★★ ⚠ same condition
CACNA1E p.Arg59Pro Uncertain significance ★★ ⚠ same condition
CACNA1E p.Arg772Gln Uncertain significance ★★ ⚠ same condition

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/cacna1e-p-thr2012arg (accessed [today's date]).

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