Is CALR3 p.Ser53= (c.159G>A) pathogenic?

CALR3 p.Ser53= (c.159G>A) is classified Likely benign in CALR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-12). Very rare (popmax 0.00834%, amr); Associated with hypertrophic cardiomyopathy 19.

What condition is associated with CALR3 p.Ser53= (c.159G>A)?

CALR3 p.Ser53= (c.159G>A) is associated with hypertrophic cardiomyopathy 19 (ClinVar).

How common is CALR3 p.Ser53= (c.159G>A) in the general population?

CALR3 p.Ser53= (c.159G>A) is very rare (popmax 0.00834%, amr) (gnomAD).

CALR3 p.Ser53=

c.159G>A · rs372912264 · VCV1106563

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Conditions

hypertrophic cardiomyopathy 19

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.068	moderately benign-leaning
Splicing
SpliceAI	Δ0.64	donor loss · deltas
Pangolin	Δ0.51	gain · loss 0.43 · SpliceAI calls loss · independent
Constraint at this position
Conservation	phyloP -3.4	GERP -4.1
Overall
CADD	15.38	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00834% Admixed American · 5/59,978 alleles

Filtering AF 0.00386% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00353%

Overall 0.00403% 65/1,613,964 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,996
European (non-Finnish)	0.00492%	20,345
Remaining individualsnot grpmax-eligible	0.0032%	31,243

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.Ser53=
Coding: c.159G>A
MANE Select: NM_145046
dbSNP: rs372912264
Type: single nucleotide variant
Location: chr19:16495785 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.43
Residue 53: the 'n-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.Ser53Leu 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
CALR3 p.Arg308Ile Uncertain significance ★★ ⚠ same condition
CALR3 p.Arg80Cys 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-ser53 (accessed [today's date]).

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