Is CALM3 p.Phe142Leu (c.426T>G) pathogenic?

CALM3 p.Phe142Leu (c.426T>G) is classified Pathogenic in CALM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-13). AlphaMissense: likely pathogenic (0.9982); Absent from gnomAD v4.1; Associated with long QT syndrome 1.

What condition is associated with CALM3 p.Phe142Leu (c.426T>G)?

CALM3 p.Phe142Leu (c.426T>G) is associated with long QT syndrome 1 (ClinVar).

How common is CALM3 p.Phe142Leu (c.426T>G) in the general population?

CALM3 p.Phe142Leu (c.426T>G) 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.

What do computational predictors say about CALM3 p.Phe142Leu (c.426T>G)?

AlphaMissense predicts likely pathogenic (score 0.9982) — an in-silico prediction, not a clinical call.

CALM3 p.Phe142Leu

c.426T>G · rs2513646355 · VCV2138308

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9982 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

long QT syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9982	likely pathogenic ✓ concordant with ClinVar · top 2% in CALM3
REVEL	0.448	indeterminate
SaProt	LLR -12.91	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -0.39, phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 7,715 bp · p 1.4e-22 · regional, not allelic
Overall
CADD	23.6	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: CALM3
Protein: p.Phe142Leu
Coding: c.426T>G
MANE Select: NM_005184
dbSNP: rs2513646355
Type: single nucleotide variant
Location: chr19:46609129 (GRCh38)
Gene constraint: LOEUF 0.556 · pLI 0.93 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 26 PDB
Residue 142: the ef-hand 4 domain; the 'necessary and sufficient for interaction with pcp4' region; an α-helix

Full CALM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

long QT syndrome 1 — 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

CALM3 p.Phe142= Likely benign ★ same residue
CALM3 p.Asp94Ala Pathogenic/Likely pathogenic ★★ same condition
CALM3 p.Asp96His Pathogenic/Likely pathogenic ★★ same condition
CALM3 p.Glu141Lys Pathogenic ★★ same condition
CALM3 c.34+3G>A Uncertain significance ★★ same condition
CALM3 c.421+5G>A Uncertain significance ★★ same condition
CALM3 p.Ala148Thr Uncertain significance ★★ ⚠ same condition
CALM3 p.Arg107Cys 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/calm3-p-phe142leu (accessed [today's date]).

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