Is MYH7 p.Leu926Val (c.2776C>G) pathogenic?

MYH7 p.Leu926Val (c.2776C>G) is classified Uncertain significance in MYH7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-05). AlphaMissense: likely benign (0.0953); Ultra-rare (popmax 0.0253%, sas); Associated with hypertrophic cardiomyopathy.

What condition is associated with MYH7 p.Leu926Val (c.2776C>G)?

MYH7 p.Leu926Val (c.2776C>G) is associated with hypertrophic cardiomyopathy (ClinVar).

How common is MYH7 p.Leu926Val (c.2776C>G) in the general population?

MYH7 p.Leu926Val (c.2776C>G) is ultra-rare (popmax 0.0253%, sas) (gnomAD).

What do computational predictors say about MYH7 p.Leu926Val (c.2776C>G)?

AlphaMissense predicts likely benign (score 0.0953) — an in-silico prediction, not a clinical call.

MYH7 p.Leu926Val

c.2776C>G · rs575013686 · VCV946399

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0953 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypertrophic cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.0953	likely benign
REVEL	0.23	benign-leaning
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -20	GERP -3.8
Regional constraint	o/e 0.89	unconstrained · MANE · 3,932 bp · p 0.061 · regional, not allelic
Overall
CADD	17.62	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0253% South Asian · 23/91,086 alleles

Filtering AF 0.0172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0146%

Overall 0.00149% 24/1,614,200 alleles · ultra-rare exomes 23/1,461,894 · genomes 1/152,306 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0253%	3,960
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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: MYH7
Protein: p.Leu926Val
Coding: c.2776C>G
MANE Select: NM_000257
dbSNP: rs575013686
Type: single nucleotide variant
Location: chr14:23424053 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 74.45 · 46 PDB
Residue 926: an α-helix

Full MYH7 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

MYH7 p.Leu926Pro Uncertain significance ★ ⚠ same residue
MYH7 p.Leu926_Glu927delinsGln Uncertain significance ★ same residue
MYH7 p.Leu926= Likely benign ★ same residue
MYH7 p.Arg1045Leu Likely pathogenic ★★★ same condition
MYH7 p.Arg1053Gln Pathogenic ★★★ same condition
MYH7 p.Arg1193His Likely pathogenic ★★★ same condition
MYH7 p.Arg1420Trp Likely pathogenic ★★★ same condition
MYH7 p.Arg143Gln Likely pathogenic ★★★ 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-leu926val (accessed [today's date]).

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