Is CACNA1I p.Pro474= (c.1422C>T) pathogenic?

CACNA1I p.Pro474= (c.1422C>T) is classified Likely benign in CACNA1I (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-09-10). Ultra-rare (popmax 0.0121%, nfe); Associated with CACNA1I-related disorder.

What condition is associated with CACNA1I p.Pro474= (c.1422C>T)?

CACNA1I p.Pro474= (c.1422C>T) is associated with CACNA1I-related disorder (ClinVar).

How common is CACNA1I p.Pro474= (c.1422C>T) in the general population?

CACNA1I p.Pro474= (c.1422C>T) is ultra-rare (popmax 0.0121%, nfe) (gnomAD).

CACNA1I p.Pro474=

c.1422C>T · VCV3355704

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, nfe)

Conditions

CACNA1I-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -2.6
Overall
CADD	2.187	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0121% European (non-Finnish) · 138/1,139,428 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00981%

Overall 0.00999% 153/1,530,774 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0121%	8,257
East Asian	0.00982%	10,180
Remaining individualsnot grpmax-eligible	0.00677%	14,774
South Asian	0.00489%	20,458
African / African-American	0.00417%	23,982

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: CACNA1I
Protein: p.Pro474=
Coding: c.1422C>T
MANE Select: NM_021096
Type: single nucleotide variant
Location: chr22:39646841 (GRCh38)
Gene constraint: LOEUF 0.525 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.94 · 4 PDB
Residue 474: the 'disordered' region

Full CACNA1I gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CACNA1I-related disorder

Similar variants

CACNA1I p.Val1427Met Uncertain significance ★★ ⚠ same condition
CACNA1I p.Met1730Thr Likely pathogenic ★ same condition
CACNA1I p.Arg1550Ter Uncertain significance ★ same condition
CACNA1I p.Gln1553His Uncertain significance ★ ⚠ same condition
CACNA1I p.Glu1649Lys Uncertain significance ★ ⚠ same condition
CACNA1I p.Gly2163Ala Uncertain significance ★ ⚠ same condition
CACNA1I p.His2099Arg Uncertain significance ★ ⚠ same condition
CACNA1I p.Ile710Val 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/cacna1i-p-pro474 (accessed [today's date]).

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