Is CALM3 p.Asp130His (c.388G>C) pathogenic?

CALM3 p.Asp130His (c.388G>C) is classified Uncertain significance in CALM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-20). AlphaMissense: likely pathogenic (0.9973); Absent from gnomAD v4.1; Associated with long QT syndrome 1.

What condition is associated with CALM3 p.Asp130His (c.388G>C)?

CALM3 p.Asp130His (c.388G>C) is associated with long QT syndrome 1 (ClinVar).

How common is CALM3 p.Asp130His (c.388G>C) in the general population?

CALM3 p.Asp130His (c.388G>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.

What do computational predictors say about CALM3 p.Asp130His (c.388G>C)?

AlphaMissense predicts likely pathogenic (score 0.9973) — an in-silico prediction, not a clinical call.

CALM3 p.Asp130His

c.388G>C · rs1568666846 · VCV581818

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9973 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

long QT syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9973	likely pathogenic · top 6% in CALM3
REVEL	0.878	moderately pathogenic-leaning
SaProt	LLR -12.92	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 7,715 bp · p 1.4e-22 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Asp130His
Coding: c.388G>C
MANE Select: NM_005184
dbSNP: rs1568666846
Type: single nucleotide variant
Location: chr19:46608948 (GRCh38)
Gene constraint: LOEUF 0.556 · pLI 0.93 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 26 PDB
Residue 130: a binding site; a UniProt-annotated variant site (in lqt16); the ef-hand 4 domain; the 'necessary and sufficient for interaction with pcp4' region

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.Asp130= Benign ★★ same residue
CALM3 p.Asp130Glu Pathogenic ★ same residue
CALM3 p.Asp130Asn Uncertain significance ★ same residue
CALM3 p.Asp130Gly Pathogenic 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

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-asp130his (accessed [today's date]).

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