Is CACNA1C p.Pro613Arg (c.1838C>G) pathogenic?

CACNA1C p.Pro613Arg (c.1838C>G) is classified Likely pathogenic in CACNA1C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures.

How common is CACNA1C p.Pro613Arg (c.1838C>G) in the general population?

CACNA1C p.Pro613Arg (c.1838C>G) is absent from gnomAD v4.1 (gnomAD).

CACNA1C p.Pro613Arg

Q: What condition is associated with CACNA1C p.Pro613Arg (c.1838C>G)?

CACNA1C p.Pro613Arg (c.1838C>G) is associated with neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures (ClinVar).

c.1838C>G · VCV4531394

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.904	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 14 kb · p 1.2e-11 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CACNA1C
Protein: p.Pro613Arg
Coding: c.1838C>G
MANE Select: NM_000719
Type: single nucleotide variant
Location: chr12:2567737 (GRCh38)
Gene constraint: LOEUF 0.186 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.73 · 33 PDB
Residue 613: a UniProt-annotated variant site (in nedhlss); an α-helix

Full CACNA1C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CACNA1C p.Pro613= Likely benign ★★ same residue
CACNA1C p.Arg1187Ter Pathogenic ★★ same condition
CACNA1C p.Gly406Arg Pathogenic ★★ same condition
CACNA1C p.Met611Thr Pathogenic/Likely pathogenic ★★ same condition
CACNA1C p.Val1363Met Likely pathogenic ★★ same condition
CACNA1C p.Arg1335Cys Uncertain significance ★★ same condition
CACNA1C p.Arg1595Gln Uncertain significance ★★ same condition
CACNA1C p.Arg1629Trp 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/cacna1c-p-pro613arg (accessed [today's date]).

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