# NM_000260.4(MYO7A):c.2372G>A (p.Arg791His)

https://sugi.bio/variant/myo7a-p-arg791his

## Summary

**MYO7A p.Arg791His (c.2372G>A)** is classified **Uncertain significance** in MYO7A (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-07-22). AlphaMissense: likely benign (0.1755); Very rare (popmax 0.00958%, afr); Associated with Usher syndrome type 1.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs782693893 · 6 submitters · 4 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00958%, afr)

## For patients & families {#patients}

This is a change in the MYO7A gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 6 submitters, and is linked to Usher syndrome type 1.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Worldwide) |
| Diagnostic panels | MYO7A is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Usher syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Sensorineural hearing impairment — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Abnormal electroretinogram — Very frequent (99-80%)
- Progressive visual loss — Very frequent (99-80%)
- Blindness — Very frequent (99-80%)
- Nyctalopia — Very frequent (99-80%)
- Visual field defect — Very frequent (99-80%)
- Abnormal vestibular function — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005435/index) · [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.Arg791His |
| Coding change (HGVS c.) | c.2372G>A |
| MANE Select transcript | [NM_000260](https://www.ncbi.nlm.nih.gov/nuccore/NM_000260) |
| dbSNP | [rs782693893](https://www.ncbi.nlm.nih.gov/snp/rs782693893/) |
| Variant type | single nucleotide variant |
| Location | chr11:77179739-77179739 (GRCh38) |
| ClinVar | [VCV306175](https://www.ncbi.nlm.nih.gov/clinvar/variation/306175/) |

**All HGVS expressions:** `LRG_1420:g.56494G>A`, `LRG_1420t1:c.2372G>A`, `NC_000011.10:g.77179739G>A`, `NC_000011.9:g.76890785G>A`, `NG_009086.2:g.56494G>A`, `NM_000260.4:c.2372G>A`, `NM_001127180.2:c.2372G>A`, `NM_001369365.1:c.2339G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1755)
- REVEL 0.514 (indeterminate)
- SaProt LLR -10.768 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate
- Conservation: phyloP 6.649, GERP 1.6, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.3**. 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 0.95** across the covering region of the MANE Select transcript (77,130,635–77,214,693), spanning 84,058 bp. Chi-square p 0.0065. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00958%** (afr) · FAF95 0.00447% · FAF99 0.00315% · 7/73,050 in the highest group · 54/1,541,434 alleles overall — very rare (popmax 0.00958%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00958% | 10,436 |
| Remaining individuals (not grpmax-eligible) | 0.00502% | 19,905 |
| European (non-Finnish) | 0.00359% | 27,872 |
| East Asian | 0.00244% | 40,986 |
| South Asian | 0.00239% | 41,900 |

*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 **791** lies in the iq 3 domain.

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.Arg791His falls in the iq 3 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-22.

**Submitter consensus:** unanimous (8/8 Uncertain significance).

**Submission history:** 8 submissions (2018–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-16 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-04-25 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2019-11-11 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-22 |

## Associated conditions {#conditions}

[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/), [Usher syndrome type 1B](https://sugi.bio/atlas/disease/usher-syndrome-type-1b/).

**Reported phenotype names (ClinVar):** Usher syndrome type 1, Autosomal dominant nonsyndromic hearing loss 11, Autosomal recessive nonsyndromic hearing loss 2, not provided, Usher syndrome type 1B, Inborn genetic diseases, RETINITIS PIGMENTOSA AND CONGENITAL DEAFNESS, Usher syndrome type IB, none provided, NEUROSENSORY NONSYNDROMIC RECESSIVE DEAFNESS 2.

## Similar variants {#similar}

Related MYO7A variant pages (same residue, condition, or type): [MYO7A p.Arg791Cys](/variant/myo7a-p-arg791cys), [MYO7A p.Arg791Pro](/variant/myo7a-p-arg791pro), [MYO7A p.Ala1288Pro](/variant/myo7a-p-ala1288pro), [MYO7A p.Arg1168Gln](/variant/myo7a-p-arg1168gln), [MYO7A p.Arg1873Gln](/variant/myo7a-p-arg1873gln), [MYO7A p.Arg395Cys](/variant/myo7a-p-arg395cys), [MYO7A p.Arg668Cys](/variant/myo7a-p-arg668cys), [MYO7A p.Arg853His](/variant/myo7a-p-arg853his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 306175). 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.*