# NM_206933.4(USH2A):c.991dup (p.Arg331fs)

https://sugi.bio/variant/ush2a-p-arg331fs

## Summary

**USH2A p.Arg331fs (c.991dup)** is classified **Pathogenic** in USH2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-11). Associated with Usher syndrome type 2A.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the USH2A gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Usher syndrome type 2A.

*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 | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015241/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [USH2A](https://sugi.bio/atlas/gene/USH2A/) |
| Protein change (HGVS p.) | p.Arg331fs |
| Coding change (HGVS c.) | c.991dup |
| MANE Select transcript | [NM_206933](https://www.ncbi.nlm.nih.gov/nuccore/NM_206933) |
| Variant type | Duplication |
| Location | chr1:216325456-216325457 (GRCh38) |
| ClinVar | [VCV4531389](https://www.ncbi.nlm.nih.gov/clinvar/variation/4531389/) |

**All HGVS expressions:** `NC_000001.10:g.216498799dup`, `NC_000001.11:g.216325457dup`, `NG_009497.2:g.102992dup`, `NM_007123.6:c.991dup`, `NM_206933.4:c.991dup`

## Computational & population evidence {#evidence}

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

- **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 -0.036, GERP -0.366 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.855, pLI 2.7327e-115. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 72**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**USH2A** population constraint: LOEUF 0.855, pLI 2.7327e-115, missense-Z 0.11215; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/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):

- **Usher syndrome type 2** — Definitive (AR)

## Protein context {#protein}

Residue **331** lies in the laminin n-terminal domain.

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

*Describes the biological roles of USH2A (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:** USH2A's established molecular role includes collagen binding. p.Arg331fs falls in the laminin n-terminal domain.


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

**Molecular function:** collagen binding, myosin binding.

**Biological process:** sensory perception of sound, photoreceptor cell maintenance, maintenance of animal organ identity, sensory perception of light stimulus, inner ear receptor cell differentiation.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-11.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-11 |

## Associated conditions {#conditions}

[Usher syndrome type 2A](https://sugi.bio/atlas/disease/usher-syndrome-type-2a/).

**Reported phenotype names (ClinVar):** Usher syndrome type 2A, RETINAL DISEASE IN USHER SYNDROME TYPE IIA, MODIFIER OF, USHER SYNDROME, TYPE IIA.

## Same-residue context {#hotspot}

Residue **331** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [USH2A p.Arg331Ter](/variant/ush2a-p-arg331ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related USH2A variant pages (same residue, condition, or type): [USH2A p.Arg331Ter](/variant/ush2a-p-arg331ter), [USH2A p.Arg1504fs](/variant/ush2a-p-arg1504fs), [USH2A p.Ala1214fs](/variant/ush2a-p-ala1214fs), [USH2A p.Ala1717fs](/variant/ush2a-p-ala1717fs), [USH2A p.Ala4678fs](/variant/ush2a-p-ala4678fs), [USH2A p.Arg1946fs](/variant/ush2a-p-arg1946fs), [USH2A p.Arg205fs](/variant/ush2a-p-arg205fs), [USH2A p.Asn2377fs](/variant/ush2a-p-asn2377fs).

### 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 4531389). 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.*