Is MYBPC3 p.Arg1022Pro (c.3065G>C) pathogenic?

MYBPC3 p.Arg1022Pro (c.3065G>C) is classified Conflicting classifications of pathogenicity in MYBPC3 (ClinVar, Conflicting submitters, 18 submitters; last evaluated 2026-07-21). AlphaMissense: likely pathogenic (0.964); Very rare (popmax 0.00661%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with MYBPC3 p.Arg1022Pro (c.3065G>C)?

MYBPC3 p.Arg1022Pro (c.3065G>C) is associated with Cardiovascular phenotype, cardiomyopathy, hypertrophic cardiomyopathy (ClinVar).

How common is MYBPC3 p.Arg1022Pro (c.3065G>C) in the general population?

MYBPC3 p.Arg1022Pro (c.3065G>C) is very rare (popmax 0.00661%, nfe) (gnomAD).

What do computational predictors say about MYBPC3 p.Arg1022Pro (c.3065G>C)?

AlphaMissense predicts likely pathogenic (score 0.964) — an in-silico prediction, not a clinical call.

MYBPC3 p.Arg1022Pro

c.3065G>C · rs397516000 · VCV42682

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 18 submitters

AlphaMissense

likely pathogenic

0.964 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00661%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.964	likely pathogenic · top 7% in MYBPC3
REVEL	0.774	moderately pathogenic-leaning
SaProt	—	withheld · numbering disagrees past residue 302 · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 21 kb · p 0.0018 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00661% European (non-Finnish) · 78/1,179,572 alleles

Filtering AF 0.00538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00498%

Overall 0.00521% 84/1,611,220 alleles · very rare exomes 78/1,458,878 · genomes 6/152,342 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00661%	15,123
Remaining individualsnot grpmax-eligible	0.0048%	20,819
African / African-American	0.00266%	37,529
Admixed American	0.00167%	59,996

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.Arg1022Pro
Coding: c.3065G>C
MANE Select: NM_000256
dbSNP: rs397516000
Type: single nucleotide variant
Location: chr11:47333682 (GRCh38)
Gene constraint: LOEUF 0.915 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.43 · 17 PDB
Residue 1022: the ig-like c2-type 6 domain

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 hypertrophic cardiomyopathy 4 left ventricular noncompaction 10

Similar variants

MYBPC3 p.Arg1022His Uncertain significance ★★ same residue
MYBPC3 p.Arg1022Cys Conflicting classifications of pathogenicity ★ same residue
MYBPC3 p.Arg1022Ser Uncertain significance ★ ⚠ 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-arg1022pro (accessed [today's date]).

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