# NM_000260.4(MYO7A):c.5969A>G (p.Gln1990Arg)

https://sugi.bio/variant/myo7a-p-gln1990arg

## Summary

**MYO7A p.Gln1990Arg (c.5969A>G)** is classified **Conflicting classifications of pathogenicity** in MYO7A (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-28). AlphaMissense: ambiguous (0.3656); Rare (popmax 0.292%, sas); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs560293591 · 6 submitters · 2 linked conditions · AlphaMissense ambiguous · rare (popmax 0.292%, sas)

## 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 6 submitters, and is linked to Inborn genetic diseases.

*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.Gln1990Arg |
| Coding change (HGVS c.) | c.5969A>G |
| MANE Select transcript | [NM_000260](https://www.ncbi.nlm.nih.gov/nuccore/NM_000260) |
| dbSNP | [rs560293591](https://www.ncbi.nlm.nih.gov/snp/rs560293591/) |
| Variant type | single nucleotide variant |
| Location | chr11:77208721-77208721 (GRCh38) |
| ClinVar | [VCV751273](https://www.ncbi.nlm.nih.gov/clinvar/variation/751273/) |

**All HGVS expressions:** `LRG_1420:g.85476A>G`, `LRG_1420t1:c.5969A>G`, `NC_000011.10:g.77208721A>G`, `NC_000011.9:g.76919766A>G`, `NG_009086.2:g.85476A>G`, `NM_000260.4:c.5969A>G`, `NM_001127180.2:c.5855A>G`, `NM_001369365.1:c.5822A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **ambiguous** (0.3656) — no call either way
- REVEL 0.749 (pathogenic-leaning)
- SaProt LLR -6.019 (tolerated)
- → **In-silico consensus:** REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate
- SpliceAI predicts **acceptor loss** (Δ 0.76) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 11.269, GERP 1.76, phastCons 1 — highly conserved
- CADD: **PHRED 23.3**. 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 deltas (raw): acceptor loss **0.76**, donor loss **0.00**, acceptor gain **0.03**, donor gain **0.00**. Largest is acceptor loss, 2 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.03**, 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 **0.292%** (sas) · FAF95 0.262% · FAF99 0.251% · 253/86,688 in the highest group · 276/1,587,174 alleles overall — rare (popmax 0.292%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.292% | 343 |
| Remaining individuals (not grpmax-eligible) | 0.0341% | 2,931 |
| East Asian | 0.0023% | 43,408 |
| Admixed American | 0.00177% | 56,350 |

*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 **1990** lies in the ferm 2 domain; a β-strand.

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.Gln1990Arg 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-28.

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

**Submission history:** 6 submissions (2020–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-02-13 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-18 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-08-02 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, Usher syndrome type 1B, not specified, Usher syndrome type IB, AllHighlyPenetrant, none provided.

## Same-residue context {#hotspot}

Residue **1990** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MYO7A p.Gln1990Ter](/variant/myo7a-p-gln1990ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MYO7A variant pages (same residue, condition, or type): [MYO7A p.Gln1990Ter](/variant/myo7a-p-gln1990ter), [MYO7A p.Gln1990Glu](/variant/myo7a-p-gln1990glu), [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 751273). 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.*