Is CALM3 p.Glu83= (c.249G>A) pathogenic?

CALM3 p.Glu83= (c.249G>A) is classified Benign/Likely benign in CALM3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-20). Ultra-rare (popmax 0.0624%, eas); Associated with Cardiovascular phenotype.

What condition is associated with CALM3 p.Glu83= (c.249G>A)?

CALM3 p.Glu83= (c.249G>A) is associated with Cardiovascular phenotype, long QT syndrome 1 (ClinVar).

How common is CALM3 p.Glu83= (c.249G>A) in the general population?

CALM3 p.Glu83= (c.249G>A) is ultra-rare (popmax 0.0624%, eas) (gnomAD).

CALM3 p.Glu83=

c.249G>A · rs755348000 · VCV1166599

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0624%, eas)

Conditions

Cardiovascular phenotype

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 6.6	GERP -2.9, phastCons 1
Overall
CADD	7.981	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0624% East Asian · 28/44,896 alleles

Filtering AF 0.0443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0382%

Overall 0.00192% 31/1,614,036 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0624%	1,603
Middle Eastern	0.0164%	6,084
Admixed American	0.00167%	60,016
European (non-Finnish)	8.47e-05%	1,179,965

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: CALM3
Protein: p.Glu83=
Coding: c.249G>A
MANE Select: NM_005184
dbSNP: rs755348000
Type: single nucleotide variant
Location: chr19:46608552 (GRCh38)
Gene constraint: LOEUF 0.556 · pLI 0.93 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 26 PDB
Residue 83: the ef-hand 3 domain; an α-helix; 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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: long QT syndrome 1

Similar variants

CALM3 p.Glu83Lys Uncertain significance ★ ⚠ 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
CALM3 c.421+5G>A Uncertain significance ★★ same condition
CALM3 p.Ala148Thr Uncertain significance ★★ ⚠ same condition
CALM3 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/calm3-p-glu83 (accessed [today's date]).

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