Is CALR3 p.Ser78fs (c.231del) pathogenic?

CALR3 p.Ser78fs (c.231del) is classified Uncertain significance in CALR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-24). Very rare (popmax 8.47e-05%, nfe); Associated with hypertrophic cardiomyopathy 19.

What condition is associated with CALR3 p.Ser78fs (c.231del)?

CALR3 p.Ser78fs (c.231del) is associated with hypertrophic cardiomyopathy 19 (ClinVar).

How common is CALR3 p.Ser78fs (c.231del) in the general population?

CALR3 p.Ser78fs (c.231del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

CALR3 p.Ser78fs

c.231del · rs770476504 · VCV2727129

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

hypertrophic cardiomyopathy 19

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,034 alleles

Overall 6.84e-05% 1/1,461,886 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: CALR3
Protein: p.Ser78fs
Coding: c.231del
MANE Select: NM_145046
dbSNP: rs770476504
Type: Deletion
Location: chr19:16490533 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.43
Residue 78: 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.Ser78= Likely benign ★ same residue
CALR3 p.Leu174fs Uncertain significance ★★ same condition
CALR3 c.193+1del Uncertain significance ★ same condition
CALR3 c.787-25_787-12del Uncertain significance ★ same condition
CALR3 c.918+14_918+30del Uncertain significance ★ same condition
CALR3 p.Asp140fs Uncertain significance ★ same condition
CALR3 p.Gln189fs Conflicting classifications of pathogenicity ★ same condition
CALR3 p.Glu361fs 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-ser78fs (accessed [today's date]).

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