Is CALM2 c.421+8T>C pathogenic?

CALM2 c.421+8T>C is classified Likely benign in CALM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-14). Very rare (popmax 0.0017%, amr); Associated with long QT syndrome 1.

What condition is associated with CALM2 c.421+8T>C?

CALM2 c.421+8T>C is associated with long QT syndrome 1 (ClinVar).

How common is CALM2 c.421+8T>C in the general population?

CALM2 c.421+8T>C is very rare (popmax 0.0017%, 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 c.421+8T>C

rs2465707007 · VCV2703155

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0017%, amr)

Conditions

long QT syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +8	near-intronic (+8 nt from the splice site)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.27	GERP -4.2
Non-coding constraint	Z 0.89	1 kb window · o/e 0.92 · regional · uncalibrated
Overall
CADD	2.419	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0017% Admixed American · 1/58,930 alleles

Overall 0.000137% 2/1,454,728 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0017%	58,930
European (non-Finnish)	8.49e-05%	1,177,761

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
Coding: c.421+8T>C
MANE Select: NM_001743
dbSNP: rs2465707007
Type: single nucleotide variant
Location: chr2:47161715 (GRCh38)
Gene constraint: LOEUF 0.262 · pLI 0.99 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.82 · 21 PDB

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-c-421-plus-8t-c (accessed [today's date]).

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