Is CALM2 p.Ala148fs (c.441_*4del) pathogenic?

CALM2 p.Ala148fs (c.4414del) is classified Uncertain significance in CALM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-31). Absent from gnomAD; Associated with long QT syndrome 1.

What condition is associated with CALM2 p.Ala148fs (c.441_*4del)?

CALM2 p.Ala148fs (c.441_*4del) is associated with long QT syndrome 1 (ClinVar).

How common is CALM2 p.Ala148fs (c.441_*4del) in the general population?

CALM2 p.Ala148fs (c.441_*4del) is absent from gnomAD (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.Ala148fs

c.441_*4del · rs2465704121 · VCV2714374

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

long QT syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	escapes	premature termination codon in the last exon (6 of 6) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.29	GERP -4.4, phastCons 0.99

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CALM2
Protein: p.Ala148fs
Coding: c.441_*4del
MANE Select: NM_001743
dbSNP: rs2465704121
Type: Deletion
Location: chr2:47160772 (GRCh38)
Gene constraint: LOEUF 0.262 · pLI 0.99 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.82 · 21 PDB
Residue 148: the ef-hand 4 domain; the 'necessary and sufficient for interaction with pcp4' region

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 c.178+10del Likely benign ★ same condition
CALM2 c.179-29_179-10del Likely benign ★ same condition
CALM2 c.285+14_285+20del Likely benign ★ same condition
CALM2 c.286-6del Benign ★ same condition
CALM2 c.3+9_3+18del Likely benign ★ same condition
CALM2 c.422-13del Likely benign ★ same condition
CALM2 c.422-9del Likely benign ★ same condition
CALM2 p.Ala148= Likely benign ★ same residue

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-ala148fs (accessed [today's date]).

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