Is CALR3 p.Arg356= (c.1068C>T) pathogenic?

CALR3 p.Arg356= (c.1068C>T) is classified Likely benign in CALR3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-24). Very rare (popmax 0.00334%, amr); Associated with hypertrophic cardiomyopathy 19.

What condition is associated with CALR3 p.Arg356= (c.1068C>T)?

CALR3 p.Arg356= (c.1068C>T) is associated with hypertrophic cardiomyopathy 19 (ClinVar).

How common is CALR3 p.Arg356= (c.1068C>T) in the general population?

CALR3 p.Arg356= (c.1068C>T) is very rare (popmax 0.00334%, amr) (gnomAD).

CALR3 p.Arg356=

c.1068C>T · rs148039385 · VCV2724046

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Conditions

hypertrophic cardiomyopathy 19

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 -9.2	GERP -4.3
Overall
CADD	0.055	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% Admixed American · 2/59,934 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00167% 27/1,613,762 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,967
South Asian	0.00329%	30,357
Finnishnot grpmax-eligible	0.00313%	31,992
Remaining individualsnot grpmax-eligible	0.0016%	62,476
European (non-Finnish)	0.00153%	65,554
African / African-American	0.00134%	74,826

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: CALR3
Protein: p.Arg356=
Coding: c.1068C>T
MANE Select: NM_145046
dbSNP: rs148039385
Type: single nucleotide variant
Location: chr19:16479218 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.43
Residue 356: the 'c-domain' region

Full CALR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypertrophic cardiomyopathy 19 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CALR3 p.Arg356Leu Benign ★★ same residue
CALR3 p.Arg356Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CALR3 p.Arg356His Uncertain significance ★ ⚠ same residue
CALR3 p.Ala331Val Uncertain significance ★★ ⚠ same condition
CALR3 p.Ala348Val Uncertain significance ★★ ⚠ same condition
CALR3 p.Arg278Cys Uncertain significance ★★ ⚠ same condition
CALR3 p.Arg278His Uncertain significance ★★ ⚠ same condition
CALR3 p.Arg278Leu 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/calr3-p-arg356 (accessed [today's date]).

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