Is CACNA1S p.Arg900Ser (c.2700G>T) pathogenic?

CACNA1S p.Arg900Ser (c.2700G>T) is classified Conflicting classifications of pathogenicity in CACNA1S (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-01-27). AlphaMissense: likely pathogenic (0.971); Absent from gnomAD v4.1; Associated with malignant hyperthermia, susceptibility to, 1.

What condition is associated with CACNA1S p.Arg900Ser (c.2700G>T)?

CACNA1S p.Arg900Ser (c.2700G>T) is associated with malignant hyperthermia, susceptibility to, 1, malignant hyperthermia, susceptibility to, 5, hypokalemic periodic paralysis, type 1 (ClinVar).

How common is CACNA1S p.Arg900Ser (c.2700G>T) in the general population?

CACNA1S p.Arg900Ser (c.2700G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CACNA1S p.Arg900Ser (c.2700G>T)?

AlphaMissense predicts likely pathogenic (score 0.971) — an in-silico prediction, not a clinical call.

CACNA1S p.Arg900Ser

c.2700G>T · rs2102582533 · VCV1503945

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.971 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

malignant hyperthermia, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.971	likely pathogenic · top 9% in CACNA1S
REVEL	0.889	moderately pathogenic-leaning
SaProt	LLR -14.88	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -2.2, phastCons 0.001
Regional constraint	o/e 0.97	unconstrained · MANE · 73 kb · p 0.13 · regional, not allelic
Overall
CADD	23.9	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

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: CACNA1S
Protein: p.Arg900Ser
Coding: c.2700G>T
MANE Select: NM_000069
dbSNP: rs2102582533
Type: single nucleotide variant
Location: chr1:201066274 (GRCh38)
Gene constraint: LOEUF 0.651 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 72.36 · 2 PDB
Residue 900: a UniProt-annotated variant site (in hokpp1)

Full CACNA1S gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

malignant hyperthermia, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: malignant hyperthermia, susceptibility to, 5 hypokalemic periodic paralysis, type 1

Similar variants

CACNA1S p.Arg900Met Pathogenic ★ same residue
CACNA1S p.Arg900Gly Uncertain significance ★ ⚠ same residue
CACNA1S c.1233-1G>A Likely pathogenic ★★ same condition
CACNA1S c.258+2T>C Likely pathogenic ★★ same condition
CACNA1S c.4113+1G>A Pathogenic/Likely pathogenic ★★ same condition
CACNA1S c.4113+1G>C Likely pathogenic ★★ same condition
CACNA1S p.Arg1086Ser Likely pathogenic ★★ same condition
CACNA1S p.Arg1239Gly Pathogenic ★★ 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/cacna1s-p-arg900ser (accessed [today's date]).

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