Is CALM2 p.Asn98Ser (c.293A>G) pathogenic?

CALM2 p.Asn98Ser (c.293A>G) is classified Pathogenic in CALM2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-05-27). Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with CALM2 p.Asn98Ser (c.293A>G)?

CALM2 p.Asn98Ser (c.293A>G) is associated with Cardiovascular phenotype, long QT syndrome, long QT syndrome 15 (ClinVar).

How common is CALM2 p.Asn98Ser (c.293A>G) in the general population?

CALM2 p.Asn98Ser (c.293A>G) is absent from gnomAD v4.1 (gnomAD).

CALM2 p.Asn98Ser

c.293A>G · rs398124647 · VCV96720

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.831	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.21	constrained · MANE · 16 kb · p 6.7e-26 · regional, not allelic
Overall
CADD	25.5	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: CALM2
Protein: p.Asn98Ser
Coding: c.293A>G
MANE Select: NM_001743
dbSNP: rs398124647
Type: single nucleotide variant
Location: chr2:47161851 (GRCh38)
Gene constraint: LOEUF 0.262 · pLI 0.99 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.82 · 21 PDB
Residue 98: a binding site; the ef-hand 3 domain; a UniProt-annotated variant site (in lqt15; reduction in calcium affinity); a UniProt-annotated variant site (in lqt15; the mutant has significantly reduced calcium affinity compared to wild-type; calmodulin-ryr2 interaction is defective at low intracellular ca(2+) concentrations and restored at moderate to high ca(2+) concentrations; increased ryr2 calcium-release channel activity; decreased calcium-dependent inactivation of l-type calcium channel; not changed protein abundance; not changed structure; significantly reduced ryanodine-sensitive calcium-release channel activity; decreased of kcnn2 calcium-activated potassium channel activity; not changed kcnn2 expression; not changed kcnn2 location at membrane); a β-strand; the 'necessary and sufficient for interaction with pcp4' region

Full CALM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: long QT syndrome long QT syndrome 15 long QT syndrome 1

Similar variants

CALM2 p.Asn98Ile Pathogenic ★ same residue
CALM2 p.Asp134Asn Likely pathogenic ★★ same condition
CALM2 p.Asp96Tyr Pathogenic/Likely pathogenic ★★ same condition
CALM2 p.Asp96Val Pathogenic ★★ same condition
CALM2 c.285+5G>A Uncertain significance ★★ same condition
CALM2 c.-2G>C Uncertain significance ★★ same condition
CALM2 c.-4C>T Uncertain significance ★★ same condition
CALM2 p.Ala58Pro 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/calm2-p-asn98ser (accessed [today's date]).

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