Is CALM3 p.Ile28Val (c.82A>G) pathogenic?

CALM3 p.Ile28Val (c.82A>G) is classified Uncertain significance in CALM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-12). AlphaMissense: ambiguous (0.3769); Very rare (popmax 0.000509%, nfe); Associated with long QT syndrome 1.

What condition is associated with CALM3 p.Ile28Val (c.82A>G)?

CALM3 p.Ile28Val (c.82A>G) is associated with long QT syndrome 1 (ClinVar).

How common is CALM3 p.Ile28Val (c.82A>G) in the general population?

CALM3 p.Ile28Val (c.82A>G) is very rare (popmax 0.000509%, nfe) (gnomAD).

How is Romano-Ward syndrome inherited?

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

What do computational predictors say about CALM3 p.Ile28Val (c.82A>G)?

AlphaMissense predicts ambiguous (score 0.3769) — an in-silico prediction, not a clinical call.

CALM3 p.Ile28Val

c.82A>G · VCV3713524

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3769 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Conditions

long QT syndrome 1

Computational evidence

Protein change
AlphaMissense	0.3769	ambiguous
REVEL	0.589	indeterminate
SaProt	LLR -12.17	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 7,715 bp · p 1.4e-22 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000509% European (non-Finnish) · 6/1,179,884 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,900 alleles · very rare

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.Ile28Val
Coding: c.82A>G
MANE Select: NM_005184
Type: single nucleotide variant
Location: chr19:46608244 (GRCh38)
Gene constraint: LOEUF 0.556 · pLI 0.93 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 26 PDB
Residue 28: the ef-hand 1 domain; a β-strand

Full CALM3 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

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
CALM3 p.Asp132Asn 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-ile28val (accessed [today's date]).

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