# NM_000260.4(MYO7A):c.6025del (p.Ala2009fs)

https://sugi.bio/variant/myo7a-p-ala2009fs

## Summary

**MYO7A p.Ala2009fs (c.6025del)** is classified **Pathogenic** in MYO7A (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-03). Very rare (popmax 0.00656%, nfe); Associated with MYO7A-related disorder.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs397516326 · 11 submitters · 6 linked conditions · very rare (popmax 0.00656%, nfe)

## For patients & families {#patients}

This is a change in the MYO7A gene that is considered disease-causing, submitted by 11 submitters, and is linked to MYO7A-related disorder.

*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.*

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

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MYO7A](https://sugi.bio/atlas/gene/MYO7A/) |
| Protein change (HGVS p.) | p.Ala2009fs |
| Coding change (HGVS c.) | c.6025del |
| MANE Select transcript | [NM_000260](https://www.ncbi.nlm.nih.gov/nuccore/NM_000260) |
| dbSNP | [rs397516326](https://www.ncbi.nlm.nih.gov/snp/rs397516326/) |
| Variant type | Deletion |
| Location | chr11:77208776-77208776 (GRCh38) |
| ClinVar | [VCV43313](https://www.ncbi.nlm.nih.gov/clinvar/variation/43313/) |

**All HGVS expressions:** `LRG_1420:g.85532del`, `LRG_1420t1:c.6025del`, `NC_000011.10:g.77208777del`, `NC_000011.9:g.76919822del`, `NG_009086.2:g.85532del`, `NM_000260.3:c.6025del`, `NM_000260.4:c.6025del`, `NM_000260.4:c.6025delG`, `NM_001127180.2:c.5911del`, `NM_001369365.1:c.5878del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 4.243, GERP -0.672, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.995, pLI 2.4072e-62. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 44 of 49**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 35.0**. 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.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00656%** (nfe) · FAF95 0.00537% · FAF99 0.0049% · 76/1,159,370 in the highest group · 79/1,573,846 alleles overall — very rare (popmax 0.00656%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00656% | 15,255 |
| Remaining individuals (not grpmax-eligible) | 0.00492% | 20,333 |

*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}

**MYO7A** population constraint: LOEUF 0.995, pLI 2.4072e-62, missense-Z 0.076546. *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):

- **Usher syndrome type 1** — Definitive (AR)
- **nonsyndromic genetic hearing loss** — Definitive (AD)

## Protein context {#protein}

Residue **2009** lies in the ferm 2 domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 77.73, 16% of residues very-high.

**1 experimental structure(s)** (PDB): [5MV9](https://www.rcsb.org/structure/5MV9).

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

*Describes the biological roles of MYO7A (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:** MYO7A's established molecular role includes microfilament motor activity. p.Ala2009fs falls in the ferm 2 domain.


### Pathways affected {#pathways}

MYO7A participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [The canonical retinoid cycle in rods (twilight vision)](https://reactome.org/content/detail/R-HSA-2453902) | curated |
| [Sensory processing of sound by inner hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662360) | electronic |
| [Sensory processing of sound by outer hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662361) | electronic |

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

**Molecular function:** microfilament motor activity, calmodulin binding, spectrin binding, actin filament binding.

**Biological process:** lysosome organization, visual perception, sensory perception of sound, actin filament-based movement, sensory perception of light stimulus, equilibrioception.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-03.

**Submitter consensus:** unanimous (12/12 Pathogenic).

**Submission history:** 12 submissions (2015–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-17 |
| Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals | Pathogenic | no assertion criteria provided | clinical testing | 2015-01-30 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2016-03-17 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-05-10 |
| Counsyl | Pathogenic | no assertion criteria provided | clinical testing | 2017-07-07 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-05 |
| Centre of Medical Genetics, University Hospital Muenster | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-18 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2026-02-03 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-04 |
| Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Pathogenic | criteria provided, single submitter | clinical testing | 2018-01-01 |

## Associated conditions {#conditions}

[MYO7A-related disorder](https://sugi.bio/atlas/disease/myo7a-related-disorder/), [Usher syndrome type 1](https://sugi.bio/atlas/disease/usher-syndrome-type-1/), [autosomal recessive nonsyndromic hearing loss 2](https://sugi.bio/atlas/disease/autosomal-recessive-nonsyndromic-hearing-loss-2/), [autosomal dominant nonsyndromic hearing loss 11](https://sugi.bio/atlas/disease/autosomal-dominant-nonsyndromic-hearing-loss-11/), [inherited retinal dystrophy](https://sugi.bio/atlas/disease/inherited-retinal-dystrophy/), [Usher syndrome type 1B](https://sugi.bio/atlas/disease/usher-syndrome-type-1b/).

**Reported phenotype names (ClinVar):** MYO7A-related disorder, Usher syndrome type 1, Rare genetic deafness, Autosomal recessive nonsyndromic hearing loss 2, not provided, Retinal dystrophy, Usher syndrome type 1B, Autosomal dominant nonsyndromic hearing loss 11, See cases, MYO7A-related disorders.

## Same-residue context {#hotspot}

Residue **2009** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MYO7A p.Ala2009Thr](/variant/myo7a-p-ala2009thr). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MYO7A variant pages (same residue, condition, or type): [MYO7A p.Ala2009Thr](/variant/myo7a-p-ala2009thr), [MYO7A p.Ala2009Asp](/variant/myo7a-p-ala2009asp), [MYO7A c.3503+12_3503+33del](/variant/myo7a-c-3503-plus-12-3503-plus-33del), [MYO7A c.2187+2_2187+8del](/variant/myo7a-c-2187-plus-2-2187-plus-8del), [MYO7A c.2283-2_2293del](/variant/myo7a-c-2283-minus-2-2293del), [MYO7A c.5471_5480+5del](/variant/myo7a-c-5471-5480-plus-5del), [MYO7A p.Ala1277fs](/variant/myo7a-p-ala1277fs), [MYO7A p.Ala202fs](/variant/myo7a-p-ala202fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 43313). 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.*