Is CALR3 p.Phe23Ile (c.67T>A) pathogenic?

CALR3 p.Phe23Ile (c.67T>A) is classified Uncertain significance in CALR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely pathogenic (0.6706); Very rare (popmax 0.00672%, nfe); Associated with hypertrophic cardiomyopathy 19.

What condition is associated with CALR3 p.Phe23Ile (c.67T>A)?

CALR3 p.Phe23Ile (c.67T>A) is associated with hypertrophic cardiomyopathy 19 (ClinVar).

How common is CALR3 p.Phe23Ile (c.67T>A) in the general population?

CALR3 p.Phe23Ile (c.67T>A) is very rare (popmax 0.00672%, nfe) (gnomAD).

What do computational predictors say about CALR3 p.Phe23Ile (c.67T>A)?

AlphaMissense predicts likely pathogenic (score 0.6706) — an in-silico prediction, not a clinical call.

CALR3 p.Phe23Ile

c.67T>A · rs368506422 · VCV180292

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6706 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00672%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypertrophic cardiomyopathy 19

Computational evidence

Protein change
AlphaMissense	0.6706	likely pathogenic
REVEL	0.629	indeterminate
SaProt	LLR -14.11	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 17 kb · p 0.24 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00672% European (non-Finnish) · 79/1,174,804 alleles

Filtering AF 0.00549% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00508%

Overall 0.00505% 81/1,603,114 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00672%	14,871
Remaining individualsnot grpmax-eligible	0.00322%	31,012

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.Phe23Ile
Coding: c.67T>A
MANE Select: NM_145046
dbSNP: rs368506422
Type: single nucleotide variant
Location: chr19:16496063 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.43
Residue 23: 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.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
CALR3 p.Asp242His 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-phe23ile (accessed [today's date]).

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