Is MYH7 p.Leu725Pro (c.2174T>C) pathogenic?

MYH7 p.Leu725Pro (c.2174T>C) is classified Likely pathogenic in MYH7 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9989); Absent from gnomAD v4.1; Associated with familial cardiomyopathy.

What condition is associated with MYH7 p.Leu725Pro (c.2174T>C)?

MYH7 p.Leu725Pro (c.2174T>C) is associated with familial cardiomyopathy (ClinVar).

How common is MYH7 p.Leu725Pro (c.2174T>C) in the general population?

MYH7 p.Leu725Pro (c.2174T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MYH7 p.Leu725Pro (c.2174T>C)?

AlphaMissense predicts likely pathogenic (score 0.9989) — an in-silico prediction, not a clinical call.

MYH7 p.Leu725Pro

c.2174T>C · rs606231335 · VCV132913

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9989 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.9989	likely pathogenic ✓ concordant with ClinVar · top 3% in MYH7
REVEL	0.89	moderately pathogenic-leaning
SaProt	LLR -16.22	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 0.99
Regional constraint	o/e 0.33	constrained · MANE · 702 bp · p 6.2e-14 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

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

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: MYH7
Protein: p.Leu725Pro
Coding: c.2174T>C
MANE Select: NM_000257
dbSNP: rs606231335
Type: single nucleotide variant
Location: chr14:23425807 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 74.45 · 46 PDB
Residue 725: the myosin motor domain; an α-helix

Full MYH7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

MYH7 p.Glu525Lys Pathogenic/Likely pathogenic ★★ same condition
MYH7 p.Val431Met Uncertain significance ★★ ⚠ same condition
MYH7 c.2163-1G>A Pathogenic ★ same condition
MYH7 p.Asp896Asn Likely pathogenic ★ same condition
MYH7 c.503-4A>G Conflicting classifications of pathogenicity ★ same condition
MYH7 c.503-8C>G Uncertain significance ★ same condition
MYH7 p.Arg723His Conflicting classifications of pathogenicity ★ ⚠ same condition
MYH7 p.His651Arg 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/myh7-p-leu725pro (accessed [today's date]).

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