# NM_000260.4(MYO7A):c.2489G>A (p.Arg830His)

https://sugi.bio/variant/myo7a-p-arg830his

## Summary

**MYO7A p.Arg830His (c.2489G>A)** is classified **Conflicting classifications of pathogenicity** in MYO7A (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2025-12-19). AlphaMissense: ambiguous (0.369); Rare (popmax 0.166%, mid); Associated with autosomal recessive nonsyndromic hearing loss 2.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs371029653 · 12 submitters · 4 linked conditions · AlphaMissense ambiguous · rare (popmax 0.166%, mid)

## For patients & families {#patients}

This is a change in the MYO7A gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 12 submitters, and is linked to autosomal recessive nonsyndromic hearing loss 2.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022582/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.Arg830His |
| Coding change (HGVS c.) | c.2489G>A |
| MANE Select transcript | [NM_000260](https://www.ncbi.nlm.nih.gov/nuccore/NM_000260) |
| dbSNP | [rs371029653](https://www.ncbi.nlm.nih.gov/snp/rs371029653/) |
| Variant type | single nucleotide variant |
| Location | chr11:77179856-77179856 (GRCh38) |
| ClinVar | [VCV191024](https://www.ncbi.nlm.nih.gov/clinvar/variation/191024/) |

**All HGVS expressions:** `LRG_1420:g.56611G>A`, `LRG_1420t1:c.2489G>A`, `NC_000011.10:g.77179856G>A`, `NC_000011.9:g.76890902G>A`, `NG_009086.2:g.56611G>A`, `NM_000260.4:c.2489G>A`, `NM_001127180.2:c.2489G>A`, `NM_001369365.1:c.2456G>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.369) — no call either way
- REVEL 0.763 (pathogenic-leaning)
- SaProt LLR -9.758 (tolerated)
- → **In-silico consensus:** REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate
- SpliceAI predicts **donor loss** (Δ 0.32) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 11.777, GERP 1.76, phastCons 1 — highly conserved
- CADD: **PHRED 33.0**. 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.*
- 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 deltas (raw): acceptor loss **0.00**, donor loss **0.32**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 5 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.166%** (mid) · FAF95 0.0866% · FAF99 0.0646% · 9/5,420 in the highest group · 133/1,541,754 alleles overall — rare (popmax 0.166%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.166% | 602 |
| Remaining individuals (not grpmax-eligible) | 0.0217% | 4,611 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.014% | 7,159 |
| European (non-Finnish) | 0.00837% | 11,946 |
| East Asian | 0.00733% | 13,644 |
| South Asian | 0.00476% | 21,003 |
| African / African-American | 0.00411% | 24,343 |
| Admixed American | 0.00196% | 50,988 |

*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 **830** lies in the iq 4 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.Arg830His falls in the iq 4 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-19.

**Submitter consensus:** conflicting (12 Uncertain significance, 3 Likely benign, 1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 17 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-10-31 |
| Genome-Nilou Lab | Likely benign | criteria provided, single submitter | clinical testing | 2021-07-14 |
| Genome-Nilou Lab | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-07-14 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | criteria provided, single submitter | research | 2023-02-26 |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2018-04-06 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Laboratory of Prof. Karen Avraham, Tel Aviv University | Pathogenic | criteria provided, single submitter | research | 2025-01-05 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-16 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-19 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-26 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely pathogenic | flagged submission | research |  |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-01-16 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely benign | criteria provided, single submitter | clinical testing | 2024-03-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-23 |

## Associated conditions {#conditions}

[autosomal recessive nonsyndromic hearing loss 2](https://sugi.bio/atlas/disease/autosomal-recessive-nonsyndromic-hearing-loss-2/), [Usher syndrome type 1](https://sugi.bio/atlas/disease/usher-syndrome-type-1/), [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):** Autosomal recessive nonsyndromic hearing loss 2, not provided, Autosomal dominant nonsyndromic hearing loss 11, Usher syndrome type 1, Usher syndrome type 1B, not specified, DEAFNESS, AUTOSOMAL RECESSIVE 2, NEUROSENSORY NONSYNDROMIC RECESSIVE DEAFNESS 2, RETINITIS PIGMENTOSA AND CONGENITAL DEAFNESS, none provided.

## Similar variants {#similar}

Related MYO7A variant pages (same residue, condition, or type): [MYO7A p.Arg830Cys](/variant/myo7a-p-arg830cys), [MYO7A p.Arg830Leu](/variant/myo7a-p-arg830leu), [MYO7A p.Arg830Ser](/variant/myo7a-p-arg830ser), [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).

### 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 191024). 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.*