Is CALR3 p.Arg80Pro (c.239G>C) pathogenic?

CALR3 p.Arg80Pro (c.239G>C) is classified Likely benign in CALR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-01-22). AlphaMissense: likely benign (0.3398); Absent from gnomAD v4.1; Associated with cardiomyopathy.

What condition is associated with CALR3 p.Arg80Pro (c.239G>C)?

CALR3 p.Arg80Pro (c.239G>C) is associated with cardiomyopathy (ClinVar).

How common is CALR3 p.Arg80Pro (c.239G>C) in the general population?

CALR3 p.Arg80Pro (c.239G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CALR3 p.Arg80Pro (c.239G>C)?

AlphaMissense predicts likely benign (score 0.3398) — an in-silico prediction, not a clinical call.

CALR3 p.Arg80Pro

c.239G>C · rs746369368 · VCV691736

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3398 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.3398	likely benign
REVEL	0.249	benign-leaning
SaProt	LLR -7.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 2.3, phastCons 0.77
Regional constraint	o/e 0.95	unconstrained · MANE · 17 kb · p 0.24 · regional, not allelic
Overall
CADD	24.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CALR3
Protein: p.Arg80Pro
Coding: c.239G>C
MANE Select: NM_145046
dbSNP: rs746369368
Type: single nucleotide variant
Location: chr19:16490525 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.43
Residue 80: the 'n-domain' region

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

Disease context

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

Similar variants

CALR3 p.Arg80Cys Uncertain significance ★★ ⚠ same residue
CALR3 p.Asp284Asn Benign/Likely benign ★★ same condition
CALR3 c.679-3dup Conflicting classifications of pathogenicity ★ same condition
CALR3 p.Lys258_Pro259delinsAlaArg Uncertain significance ★ same condition
CALR3 p.Ala331Val Uncertain significance ★★ ⚠ same type
CALR3 p.Ala348Val Uncertain significance ★★ ⚠ same type
CALR3 p.Arg278Cys Uncertain significance ★★ ⚠ same type
CALR3 p.Arg278His Uncertain significance ★★ ⚠ same type

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-arg80pro (accessed [today's date]).

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