Is CALR3 p.Thr283= (c.849C>T) pathogenic?

CALR3 p.Thr283= (c.849C>T) is classified Likely benign in CALR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-19). Ultra-rare (popmax 0.024%, afr); Associated with hypertrophic cardiomyopathy 19.

What condition is associated with CALR3 p.Thr283= (c.849C>T)?

CALR3 p.Thr283= (c.849C>T) is associated with hypertrophic cardiomyopathy 19 (ClinVar).

How common is CALR3 p.Thr283= (c.849C>T) in the general population?

CALR3 p.Thr283= (c.849C>T) is ultra-rare (popmax 0.024%, afr) (gnomAD).

CALR3 p.Thr283=

c.849C>T · rs142902333 · VCV1556893

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, afr)

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 3.3	GERP -2, phastCons 1
Overall
CADD	5.935	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.024% African / African-American · 18/74,918 alleles

Filtering AF 0.0155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.0013% 21/1,614,050 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.024%	4,162
South Asian	0.0022%	45,541
European (non-Finnish)	8.47e-05%	1,180,026

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.Thr283=
Coding: c.849C>T
MANE Select: NM_145046
dbSNP: rs142902333
Type: single nucleotide variant
Location: chr19:16482519 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.43
Residue 283: the 'p-domain' region; the '3 x approximate repeats' 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.Thr283Ile Conflicting classifications of pathogenicity ★ ⚠ 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-thr283 (accessed [today's date]).

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