# NM_206933.4(USH2A):c.1731C>T (p.Cys577=)

https://sugi.bio/variant/ush2a-p-cys577

## Summary

**USH2A p.Cys577= (c.1731C>T)** is classified **Benign/Likely benign** in USH2A (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Low-frequency (popmax 3.54%, sas); Associated with retinitis pigmentosa.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs41313732 · 8 submitters · 3 linked conditions · low-frequency (popmax 3.54%, sas)

## For patients & families {#patients}

This is a change in the USH2A gene that is classified as benign/likely benign — not considered disease-causing, submitted by 8 submitters, and is linked to retinitis pigmentosa.

*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 dominant, Autosomal recessive, Mitochondrial inheritance |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |
| Clinical trials | 238 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | USH2A is a diagnostic-grade gene on 3 Genomics England panels |

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

- Conductive hearing impairment — Very frequent (99-80%)
- Sensorineural hearing impairment — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Abnormal electroretinogram — Very frequent (99-80%)
- Retinal degeneration — Very frequent (99-80%)
- Photophobia — Very frequent (99-80%)
- Blindness — Very frequent (99-80%)
- Nystagmus — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005694/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.Cys577= |
| Coding change (HGVS c.) | c.1731C>T |
| MANE Select transcript | [NM_206933](https://www.ncbi.nlm.nih.gov/nuccore/NM_206933) |
| dbSNP | [rs41313732](https://www.ncbi.nlm.nih.gov/snp/rs41313732/) |
| Variant type | single nucleotide variant |
| Location | chr1:216292284-216292284 (GRCh38) |
| ClinVar | [VCV48474](https://www.ncbi.nlm.nih.gov/clinvar/variation/48474/) |

**All HGVS expressions:** `NC_000001.10:g.216465626G>A`, `NC_000001.11:g.216292284G>A`, `NG_009497.2:g.136165C>T`, `NM_007123.6:c.1731C>T`, `NM_206933.4:c.1731C>T`

## 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 3.801, GERP -0.352, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 9.639**. 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** — 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 **3.54%** (sas) · FAF95 3.43% · FAF99 3.39% · 3,221/91,078 in the highest group · 3,460/1,614,086 alleles overall — low-frequency (popmax 3.54%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 3.54% | 28 |
| Remaining individuals (not grpmax-eligible) | 0.28% | 357 |
| Middle Eastern | 0.264% | 379 |
| African / African-American | 0.00799% | 12,508 |
| European (non-Finnish) | 0.00339% | 29,499 |
| Admixed American | 0.00333% | 30,011 |

*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 **577** lies in a disulfide bond; the laminin egf-like 2 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.Cys577= falls in the laminin egf-like 2 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (5 Benign, 4 Likely benign).

**Submission history:** 10 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2015-07-01 |
| Natera, Inc. | Benign | no assertion criteria provided | clinical testing | 2020-09-16 |
| Genome-Nilou Lab | Likely benign | criteria provided, single submitter | clinical testing | 2023-11-04 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |

## Associated conditions {#conditions}

[retinitis pigmentosa](https://sugi.bio/atlas/disease/retinitis-pigmentosa/), [Usher syndrome type 2A](https://sugi.bio/atlas/disease/usher-syndrome-type-2a/), [retinitis pigmentosa 39](https://sugi.bio/atlas/disease/retinitis-pigmentosa-39/).

**Reported phenotype names (ClinVar):** Retinitis pigmentosa, not specified, Usher syndrome type 2A, not provided, Thyroid cancer, nonmedullary, 1, Retinitis pigmentosa 39, AllHighlyPenetrant, none provided, RETINAL DISEASE IN USHER SYNDROME TYPE IIA, MODIFIER OF, USHER SYNDROME, TYPE IIA.

## Same-residue context {#hotspot}

Residue **577** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [USH2A p.Cys577Tyr](/variant/ush2a-p-cys577tyr). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related USH2A variant pages (same residue, condition, or type): [USH2A p.Cys577Arg](/variant/ush2a-p-cys577arg), [USH2A p.Cys577Tyr](/variant/ush2a-p-cys577tyr), [USH2A c.12295-3T>A](/variant/ush2a-c-12295-minus-3t-a), [USH2A c.8559-2A>G](/variant/ush2a-c-8559-minus-2a-g), [USH2A c.8682-9A>G](/variant/ush2a-c-8682-minus-9a-g), [USH2A p.Ala4740Asp](/variant/ush2a-p-ala4740asp), [USH2A p.Arg3905Cys](/variant/ush2a-p-arg3905cys), [USH2A p.Arg4192Cys](/variant/ush2a-p-arg4192cys).

### 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 48474). 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.*