Is MYBPC3 p.Pro121= (c.363G>A) pathogenic?

MYBPC3 p.Pro121= (c.363G>A) is classified Likely benign in MYBPC3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-23). Ultra-rare (popmax 0.0109%, sas); Associated with Cardiovascular phenotype.

What condition is associated with MYBPC3 p.Pro121= (c.363G>A)?

MYBPC3 p.Pro121= (c.363G>A) is associated with Cardiovascular phenotype, cardiomyopathy, hypertrophic cardiomyopathy (ClinVar).

How common is MYBPC3 p.Pro121= (c.363G>A) in the general population?

MYBPC3 p.Pro121= (c.363G>A) is ultra-rare (popmax 0.0109%, sas) (gnomAD).

MYBPC3 p.Pro121=

c.363G>A · rs780768974 · VCV454330

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0109%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.3	GERP -2.1
Overall
CADD	6.105	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0109% South Asian · 9/82,446 alleles

Filtering AF 0.00562% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0042%

Overall 0.00283% 44/1,552,488 alleles · ultra-rare exomes 39/1,400,332 · genomes 5/152,156 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0109%	9,161
East Asian	0.00944%	10,595
Remaining individualsnot grpmax-eligible	0.00667%	14,995
European (non-Finnish)	0.00225%	44,463
Admixed American	0.00223%	44,884

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: MYBPC3
Protein: p.Pro121=
Coding: c.363G>A
MANE Select: NM_000256
dbSNP: rs780768974
Type: single nucleotide variant
Location: chr11:47350545 (GRCh38)
Gene constraint: LOEUF 0.915 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.43 · 17 PDB
Residue 121: the 'disordered' region

Full MYBPC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: cardiomyopathy hypertrophic cardiomyopathy

Similar variants

MYBPC3 p.Pro121Gln Uncertain significance ★★ ⚠ same residue
MYBPC3 p.Pro121Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MYBPC3 p.Pro121fs Pathogenic ★★ same residue
MYBPC3 p.Arg495Gln Likely pathogenic ★★★ ⚠ same condition
MYBPC3 p.Arg495Gly Likely pathogenic ★★★ ⚠ same condition
MYBPC3 p.Arg495Trp Likely pathogenic ★★★ ⚠ same condition
MYBPC3 p.Arg502Gln Pathogenic ★★★ ⚠ same condition
MYBPC3 c.26-2A>G 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/mybpc3-p-pro121 (accessed [today's date]).

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