# NM_000257.4(MYH7):c.77C>T (p.Ala26Val)

https://sugi.bio/variant/myh7-p-ala26val

## Summary

**MYH7 p.Ala26Val (c.77C>T)** is classified **Benign** in MYH7 (ClinVar, Expert panel, 19 submitters; last evaluated 2025-11-11). AlphaMissense: likely benign (0.2922); Rare (popmax 0.613%, eas); Associated with hypertrophic cardiomyopathy.

**At a glance:** Benign · review: Expert panel · rsID rs186964570 · 19 submitters · 9 linked conditions · AlphaMissense likely benign · rare (popmax 0.613%, eas)

## For patients & families {#patients}

This is a change in the MYH7 gene that is classified as benign — not considered disease-causing, submitted by 19 submitters, and is linked to hypertrophic cardiomyopathy.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 233 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MYH7](https://sugi.bio/atlas/gene/MYH7/) |
| Protein change (HGVS p.) | p.Ala26Val |
| Coding change (HGVS c.) | c.77C>T |
| MANE Select transcript | [NM_000257](https://www.ncbi.nlm.nih.gov/nuccore/NM_000257) |
| dbSNP | [rs186964570](https://www.ncbi.nlm.nih.gov/snp/rs186964570/) |
| Variant type | single nucleotide variant |
| Location | chr14:23433656-23433656 (GRCh38) |
| ClinVar | [VCV37375](https://www.ncbi.nlm.nih.gov/clinvar/variation/37375/) |

**All HGVS expressions:** `LRG_384:g.7006C>T`, `LRG_384t1:c.77C>T`, `NC_000014.8:g.23902865G>A`, `NC_000014.9:g.23433656G>A`, `NG_007884.1:g.7006C>T`, `NM_000257.4:c.77C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.2922)
- REVEL 0.573 (indeterminate)
- SaProt LLR -11.476 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate
- Conservation: phyloP 3.989, GERP 1.91, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.4**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.94** across the covering region of the MANE Select transcript (23,433,205–23,433,732), spanning 527 bp. Chi-square p 0.58. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for MYH7 (1,267 scored positions, the nearest 1 base away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.613%** (eas) · FAF95 0.553% · FAF99 0.53% · 275/44,888 in the highest group · 389/1,614,270 alleles overall — rare (popmax 0.613%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.613% | 163 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0574% | 1,742 |
| Remaining individuals (not grpmax-eligible) | 0.0256% | 3,907 |
| South Asian | 0.00768% | 13,013 |
| Admixed American | 0.00666% | 15,009 |
| European (non-Finnish) | 0.00593% | 16,858 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**MYH7** population constraint: LOEUF 0.644, pLI 1.6832e-19, missense-Z 6.8055; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **arrhythmogenic right ventricular cardiomyopathy** — Limited (AD)
- **hypertrophic cardiomyopathy** — Definitive (AD)
- **dilated cardiomyopathy 1S** — Definitive (AD)
- **MYH7-related skeletal myopathy** — Definitive (AD)

## Protein context {#protein}

Residue **26** lies in a UniProt-annotated variant site (in cmh1; benign); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 74.45, 10% of residues very-high.

**46 experimental structure(s)** (PDB): [2FXM](https://www.rcsb.org/structure/2FXM), [2FXO](https://www.rcsb.org/structure/2FXO), [3DTP](https://www.rcsb.org/structure/3DTP), [4DB1](https://www.rcsb.org/structure/4DB1), [4P7H](https://www.rcsb.org/structure/4P7H), [4PA0](https://www.rcsb.org/structure/4PA0) — incl. mutant structure 8ENC.

## What this gene does {#gene-function}

*Describes the biological roles of MYH7 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** MYH7's established molecular role includes microfilament motor activity.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** microfilament motor activity.

**Biological process:** regulation of the force of heart contraction, regulation of heart rate, skeletal muscle contraction, muscle contraction, striated muscle contraction, adult heart development.

## Clinical significance {#significance}

**Benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-11-11.

**Submitter consensus:** conflicting (14 Likely benign, 5 Benign, 3 Uncertain significance).

**Submission history:** 22 submissions (2012–2026); classifications have differed over time.

**ClinGen expert panel:** Benign — Cardiomyopathy VCEP (hypertrophic cardiomyopathy). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `BA1`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The filtering allele frequency of the c.77C>T (p.Ala26Val) variant in the MYH7 gene is 0.55% (60/8646) of East Asian chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50002 · approved 2025-11-11 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/e26a6375-f03a-4542-9924-d09781723678).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2015-08-11 |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2019-06-30 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2016-10-27 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-06-23 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-06-05 |
| CSER _CC_NCGL, University of Washington | Uncertain significance | no assertion criteria provided | research | 2014-06-01 |
| Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Benign | criteria provided, single submitter | research | 2013-06-24 |
| Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Uncertain significance | criteria provided, single submitter | reference population | 2016-03-18 |
| Color Diagnostics, LLC DBA Color Health | Benign | criteria provided, single submitter | clinical testing | 2018-07-09 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2012-12-12 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Uncertain significance | criteria provided, single submitter | clinical testing | 2015-10-12 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-05-24 |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-08 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-08-08 |
| ClinGen Cardiomyopathy Variant Curation Expert Panel | Benign | reviewed by expert panel | curation | 2025-11-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-10 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-04-01 |
| Stanford Center for Inherited Cardiovascular Disease, Stanford University | Likely benign | criteria provided, single submitter | provider interpretation | 2016-08-22 |

## Associated conditions {#conditions}

[hypertrophic cardiomyopathy](https://sugi.bio/atlas/disease/hypertrophic-cardiomyopathy/), [cardiomyopathy](https://sugi.bio/atlas/disease/cardiomyopathy/), [MYH7-related skeletal myopathy](https://sugi.bio/atlas/disease/myh7-related-skeletal-myopathy/), [congenital myopathy 7A, myosin storage, autosomal dominant](https://sugi.bio/atlas/disease/congenital-myopathy-7a-myosin-storage-autosomal-dominant/), [hypertrophic cardiomyopathy 1](https://sugi.bio/atlas/disease/hypertrophic-cardiomyopathy-1/), [myopathy, myosin storage, autosomal recessive](https://sugi.bio/atlas/disease/myopathy-myosin-storage-autosomal-recessive/), [congenital fiber-type disproportion myopathy](https://sugi.bio/atlas/disease/congenital-fiber-type-disproportion-myopathy/), [dilated cardiomyopathy 1S](https://sugi.bio/atlas/disease/dilated-cardiomyopathy-1s/), [familial hypertrophic cardiomyopathy](https://sugi.bio/atlas/disease/familial-hypertrophic-cardiomyopathy/).

**Reported phenotype names (ClinVar):** Hypertrophic cardiomyopathy, not specified, Hypertrophic cardiomyopathy 1, Primary familial hypertrophic cardiomyopathy, Dilated cardiomyopathy 1S, MYH7-related skeletal myopathy, not provided, Cardiomyopathy, Cardiovascular phenotype, Congenital myopathy with fiber type disproportion.

## Similar variants {#similar}

Related MYH7 variant pages (same residue, condition, or type): [MYH7 p.Ala26Thr](/variant/myh7-p-ala26thr), [MYH7 p.Ala26=](/variant/myh7-p-ala26), [MYH7 p.Arg1045Leu](/variant/myh7-p-arg1045leu), [MYH7 p.Arg1053Gln](/variant/myh7-p-arg1053gln), [MYH7 p.Arg1193His](/variant/myh7-p-arg1193his), [MYH7 p.Arg1420Trp](/variant/myh7-p-arg1420trp), [MYH7 p.Arg143Gln](/variant/myh7-p-arg143gln), [MYH7 p.Arg143Trp](/variant/myh7-p-arg143trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 37375). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*