Is CACNB1 p.Pro14His (c.41C>A) pathogenic?

CACNB1 p.Pro14His (c.41C>A) is classified Uncertain significance in CACNB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: likely benign (0.0873); Ultra-rare (popmax 0.0279%, amr).

How common is CACNB1 p.Pro14His (c.41C>A) in the general population?

CACNB1 p.Pro14His (c.41C>A) is ultra-rare (popmax 0.0279%, amr) (gnomAD).

What do computational predictors say about CACNB1 p.Pro14His (c.41C>A)?

AlphaMissense predicts likely benign (score 0.0873) — an in-silico prediction, not a clinical call.

CACNB1 p.Pro14His

c.41C>A · VCV3994590

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0873 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0279%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0873	likely benign
REVEL	0.282	benign-leaning
SaProt	LLR -7.32	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 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 22 kb · p 2.7e-10 · regional, not allelic
Overall
CADD	25.1	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 0.0279% Admixed American · 10/35,780 alleles

Filtering AF 0.0152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0115%

Overall 0.000674% 10/1,484,756 alleles · ultra-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: CACNB1
Protein: p.Pro14His
Coding: c.41C>A
MANE Select: NM_000723
Type: single nucleotide variant
Location: chr17:39197455 (GRCh38)
Gene constraint: LOEUF 0.556 · pLI 0.58 (gnomAD)
Structure: AlphaFold pLDDT 69.79 · 6 PDB
Residue 14: the 'disordered' region

Full CACNB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CACNB1 p.Arg487= Benign ★★ same type
CACNB1 p.Ser464= Benign ★★ same type
CACNB1 p.Ala323Gly Uncertain significance ★ same type
CACNB1 p.Ala330Thr Uncertain significance ★ ⚠ same type
CACNB1 p.Ala372Val Uncertain significance ★ ⚠ same type
CACNB1 p.Ala407Thr Uncertain significance ★ ⚠ same type
CACNB1 p.Ala543Asp Uncertain significance ★ ⚠ same type
CACNB1 p.Ala80Gly 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/cacnb1-p-pro14his (accessed [today's date]).

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