Is CALM2 p.Asn112= (c.336C>T) pathogenic?

CALM2 p.Asn112= (c.336C>T) is classified Likely benign in CALM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-15). Ultra-rare (popmax 0.01%, amr); Associated with long QT syndrome 1.

What condition is associated with CALM2 p.Asn112= (c.336C>T)?

CALM2 p.Asn112= (c.336C>T) is associated with long QT syndrome 1 (ClinVar).

How common is CALM2 p.Asn112= (c.336C>T) in the general population?

CALM2 p.Asn112= (c.336C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

How is Romano-Ward syndrome inherited?

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

CALM2 p.Asn112=

c.336C>T · rs751334551 · VCV1136043

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Conditions

long QT syndrome 1

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 8.7	GERP 2.2, phastCons 1
Overall
CADD	10.06	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,860 alleles

Filtering AF 0.00429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00296%

Overall 0.00062% 10/1,612,724 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,977
Remaining individualsnot grpmax-eligible	0.0016%	62,448
European (non-Finnish)	0.000254%	393,096

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: CALM2
Protein: p.Asn112=
Coding: c.336C>T
MANE Select: NM_001743
dbSNP: rs751334551
Type: single nucleotide variant
Location: chr2:47161808 (GRCh38)
Gene constraint: LOEUF 0.262 · pLI 0.99 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.82 · 21 PDB
Residue 112: the ef-hand 3 domain; the 'necessary and sufficient for interaction with pcp4' region; an α-helix

Full CALM2 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

CALM2 p.Asn98Ser Pathogenic ★★ same condition
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 p.Ala58Pro Uncertain significance ★★ same condition
CALM2 p.Arg107Cys Uncertain significance ★★ same condition
CALM2 p.Arg91Cys 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-asn112 (accessed [today's date]).

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