Is CALM1 p.Asp81= (c.243T>C) pathogenic?

CALM1 p.Asp81= (c.243T>C) is classified Likely benign in CALM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-19). Very rare (popmax 0.00133%, afr); Associated with long QT syndrome 14.

What condition is associated with CALM1 p.Asp81= (c.243T>C)?

CALM1 p.Asp81= (c.243T>C) is associated with long QT syndrome 14, catecholaminergic polymorphic ventricular tachycardia 4 (ClinVar).

How common is CALM1 p.Asp81= (c.243T>C) in the general population?

CALM1 p.Asp81= (c.243T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Romano-Ward syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CALM1 p.Asp81=

c.243T>C · VCV3748001

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

long QT syndrome 14

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 0.85	GERP -3.7, phastCons 1
Overall
CADD	11.69	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,032 alleles

Overall 6.84e-05% 1/1,461,032 alleles · very 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: CALM1
Protein: p.Asp81=
Coding: c.243T>C
MANE Select: NM_006888
Type: single nucleotide variant
Location: chr14:90403926 (GRCh38)
Gene constraint: LOEUF 0.276 · pLI 0.99 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.22 · 351 PDB
Residue 81: the ef-hand 3 domain; an α-helix; the 'necessary and sufficient for interaction with pcp4' region

Full CALM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

long QT syndrome 14 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: catecholaminergic polymorphic ventricular tachycardia 4

For Romano-Ward syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

CALM1 p.Asn98Ser Pathogenic/Likely pathogenic ★★ same condition
CALM1 p.Asp130Gly Pathogenic/Likely pathogenic ★★ same condition
CALM1 c.4-3T>C Uncertain significance ★★ same condition
CALM1 p.Glu120Lys Uncertain significance ★★ same condition
CALM1 c.178+18A>G Benign/Likely benign ★★ same condition
CALM1 c.179-4C>T Benign/Likely benign ★★ same condition
CALM1 c.285+15A>G Likely benign ★★ same condition
CALM1 c.34+19G>T Likely benign ★★ 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/calm1-p-asp81 (accessed [today's date]).

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