Is CACNA1S p.Asn1663Asp (c.4987A>G) pathogenic?

CACNA1S p.Asn1663Asp (c.4987A>G) is classified Conflicting classifications of pathogenicity in CACNA1S (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-08). AlphaMissense: likely benign (0.2387); Ultra-rare (popmax 0.0828%, afr); Associated with malignant hyperthermia, susceptibility to, 5.

What condition is associated with CACNA1S p.Asn1663Asp (c.4987A>G)?

CACNA1S p.Asn1663Asp (c.4987A>G) is associated with malignant hyperthermia, susceptibility to, 5, thyrotoxic periodic paralysis, susceptibility to, 1, hypokalemic periodic paralysis, type 1 (ClinVar).

How common is CACNA1S p.Asn1663Asp (c.4987A>G) in the general population?

CACNA1S p.Asn1663Asp (c.4987A>G) is ultra-rare (popmax 0.0828%, afr) (gnomAD).

What do computational predictors say about CACNA1S p.Asn1663Asp (c.4987A>G)?

AlphaMissense predicts likely benign (score 0.2387) — an in-silico prediction, not a clinical call.

CACNA1S p.Asn1663Asp

c.4987A>G · rs141618437 · VCV661824

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2387 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0828%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

malignant hyperthermia, susceptibility to, 5

Computational evidence

Protein change
AlphaMissense	0.2387	likely benign
REVEL	0.377	indeterminate
SaProt	LLR -7.89	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 7.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 73 kb · p 0.13 · regional, not allelic
Overall
CADD	23.7	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 0.0828% African / African-American · 62/74,888 alleles

Filtering AF 0.0662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0603%

Overall 0.00421% 68/1,614,026 alleles · ultra-rare exomes 29/1,461,890 · genomes 39/152,136 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0828%	1,208
Admixed American	0.00833%	11,999
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: CACNA1S
Protein: p.Asn1663Asp
Coding: c.4987A>G
MANE Select: NM_000069
dbSNP: rs141618437
Type: single nucleotide variant
Location: chr1:201043342 (GRCh38)
Gene constraint: LOEUF 0.651 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 72.36 · 2 PDB
Residue 1663: a UniProt-annotated variant site (in cmyo18)

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

Disease context

malignant hyperthermia, susceptibility to, 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thyrotoxic periodic paralysis, susceptibility to, 1 hypokalemic periodic paralysis, type 1 congenital myopathy 18

Similar variants

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
CACNA1S p.Arg1239His Pathogenic ★★ same condition
CACNA1S p.Arg1254Ter 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-asn1663asp (accessed [today's date]).

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