Is CALM2 p.Tyr139= (c.417T>C) pathogenic?

CALM2 p.Tyr139= (c.417T>C) is classified Likely benign in CALM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-09). Very rare (popmax 0.00553%, sas); Associated with long QT syndrome 1.

What condition is associated with CALM2 p.Tyr139= (c.417T>C)?

CALM2 p.Tyr139= (c.417T>C) is associated with long QT syndrome 1 (ClinVar).

How common is CALM2 p.Tyr139= (c.417T>C) in the general population?

CALM2 p.Tyr139= (c.417T>C) is very rare (popmax 0.00553%, sas) (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.Tyr139=

c.417T>C · rs2103823534 · VCV1606364

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00553%, sas)

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 2.6	GERP -0.17, phastCons 1
Overall
CADD	7.743	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00553% South Asian · 5/90,472 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.00048% 7/1,458,152 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00553%	18,094
European (non-Finnish)	0.00017%	589,539

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.Tyr139=
Coding: c.417T>C
MANE Select: NM_001743
dbSNP: rs2103823534
Type: single nucleotide variant
Location: chr2:47161727 (GRCh38)
Gene constraint: LOEUF 0.262 · pLI 0.99 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.82 · 21 PDB
Residue 139: a modified residue (phosphotyrosine); the ef-hand 4 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.Tyr139Ter Uncertain significance ★ same residue
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

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-tyr139 (accessed [today's date]).

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