Is MYBPC1 p.Phe175Ser (c.524T>C) pathogenic?

MYBPC1 p.Phe175Ser (c.524T>C) is classified Conflicting classifications of pathogenicity in MYBPC1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-06-10). AlphaMissense: likely benign (0.2675); Rare (popmax 0.579%, sas).

How common is MYBPC1 p.Phe175Ser (c.524T>C) in the general population?

MYBPC1 p.Phe175Ser (c.524T>C) is rare (popmax 0.579%, sas) (gnomAD).

What do computational predictors say about MYBPC1 p.Phe175Ser (c.524T>C)?

AlphaMissense predicts likely benign (score 0.2675) — an in-silico prediction, not a clinical call.

MYBPC1 p.Phe175Ser

c.524T>C · rs546207140 · VCV722202

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2675 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.579%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2675	likely benign
REVEL	0.291	indeterminate
SaProt	LLR -10.94	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 53 kb · p 6e-11 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F150S vs ClinVar F175S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.579% South Asian · 527/91,068 alleles

Filtering AF 0.538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.522%

Overall 0.0356% 575/1,613,562 alleles · rare exomes 533/1,461,208 · genomes 42/152,354 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.579%	173
Remaining individualsnot grpmax-eligible	0.0656%	1,524
Middle Eastern	0.0165%	6,060
Admixed American	0.00666%	15,007
European (non-Finnish)	0.00017%	589,723

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: MYBPC1
Protein: p.Phe175Ser
Coding: c.524T>C
MANE Select: NM_002465
dbSNP: rs546207140
Type: single nucleotide variant
Location: chr12:101632106 (GRCh38)
Gene constraint: LOEUF 0.433 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 150 UniProt numbering: a β-strand

Full MYBPC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MYBPC1 p.Arg265Gly Likely pathogenic ★★ ⚠ same type
MYBPC1 p.Glu248Lys Pathogenic/Likely pathogenic ★★ ⚠ same type
MYBPC1 p.Leu259Pro Pathogenic/Likely pathogenic ★★ same type
MYBPC1 p.Leu263Arg Pathogenic ★★ same type
MYBPC1 p.Ala582Asp Uncertain significance ★★ ⚠ same type
MYBPC1 p.Ala73Thr Uncertain significance ★★ ⚠ same type
MYBPC1 p.Ala968Pro Uncertain significance ★★ ⚠ same type
MYBPC1 p.Arg146Gln Uncertain significance ★★ ⚠ same type

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/mybpc1-p-phe175ser (accessed [today's date]).

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