Is CALM1 p.Phe90Leu (c.268T>C) pathogenic?

CALM1 p.Phe90Leu (c.268T>C) is classified Likely pathogenic in CALM1 (ClinVar, Single submitter, 2 submitters; last evaluated 2020-07-22). Absent from gnomAD v4.1; Associated with long QT syndrome 14.

What condition is associated with CALM1 p.Phe90Leu (c.268T>C)?

CALM1 p.Phe90Leu (c.268T>C) is associated with long QT syndrome 14 (ClinVar).

How common is CALM1 p.Phe90Leu (c.268T>C) in the general population?

CALM1 p.Phe90Leu (c.268T>C) is absent from gnomAD v4.1 (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.Phe90Leu

c.268T>C · rs730882253 · VCV183232

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

long QT syndrome 14

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.898	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.73, phastCons 1
Regional constraint	o/e 0.13	constrained · MANE · 7,483 bp · p 2.4e-32 · regional, not allelic
Overall
CADD	29.1	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: CALM1
Protein: p.Phe90Leu
Coding: c.268T>C
MANE Select: NM_006888
dbSNP: rs730882253
Type: single nucleotide variant
Location: chr14:90403951 (GRCh38)
Gene constraint: LOEUF 0.276 · pLI 0.99 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.22 · 351 PDB
Residue 90: the ef-hand 3 domain; a UniProt-annotated variant site (in lqt14; significantly decreased of kcnn2 calcium-activated potassium channel activity; not changed kcnn2 expression; not changed kcnn2 location at membrane; decreased thermal stability in presence of calcium ions; decreased interaction with ryr2); 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

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-phe90leu (accessed [today's date]).

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