Is MYBPC3 p.Pro1069Ser (c.3205C>T) pathogenic?

MYBPC3 p.Pro1069Ser (c.3205C>T) is classified Uncertain significance in MYBPC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-19). AlphaMissense: likely pathogenic (0.9538); Absent from gnomAD v4.1; Associated with hypertrophic cardiomyopathy.

What condition is associated with MYBPC3 p.Pro1069Ser (c.3205C>T)?

MYBPC3 p.Pro1069Ser (c.3205C>T) is associated with hypertrophic cardiomyopathy (ClinVar).

How common is MYBPC3 p.Pro1069Ser (c.3205C>T) in the general population?

MYBPC3 p.Pro1069Ser (c.3205C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MYBPC3 p.Pro1069Ser (c.3205C>T)?

AlphaMissense predicts likely pathogenic (score 0.9538) — an in-silico prediction, not a clinical call.

MYBPC3 p.Pro1069Ser

c.3205C>T · rs1014555110 · VCV1407171

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9538 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hypertrophic cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.9538	likely pathogenic · top 8% in MYBPC3
REVEL	0.854	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 12	GERP 0.72, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 21 kb · p 0.0018 · regional, not allelic
Overall
CADD	25.4	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 is an independent agreement signal.

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: MYBPC3
Protein: p.Pro1069Ser
Coding: c.3205C>T
MANE Select: NM_000256
dbSNP: rs1014555110
Type: single nucleotide variant
Location: chr11:47333319 (GRCh38)
Gene constraint: LOEUF 0.915 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.43 · 17 PDB
Residue 1069: the fibronectin type-iii 3 domain

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

Disease context

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

Similar variants

MYBPC3 p.Pro1069Leu Uncertain significance ★ ⚠ same residue
MYBPC3 p.Pro1069= Likely benign ★ 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
MYBPC3 p.Arg1271Ter 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-pro1069ser (accessed [today's date]).

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