# NM_206933.4(USH2A):c.1926C>T (p.Asp642=)

https://sugi.bio/variant/ush2a-p-asp642

## Summary

**USH2A p.Asp642= (c.1926C>T)** is classified **Likely benign** in USH2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-11). Very rare (popmax 0.00534%, afr).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs1159551018 · 2 submitters · very rare (popmax 0.00534%, afr)

## For patients & families {#patients}

This is a change in the USH2A gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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 | [USH2A](https://sugi.bio/atlas/gene/USH2A/) |
| Protein change (HGVS p.) | p.Asp642= |
| Coding change (HGVS c.) | c.1926C>T |
| MANE Select transcript | [NM_206933](https://www.ncbi.nlm.nih.gov/nuccore/NM_206933) |
| dbSNP | [rs1159551018](https://www.ncbi.nlm.nih.gov/snp/rs1159551018/) |
| Variant type | single nucleotide variant |
| Location | chr1:216289325-216289325 (GRCh38) |
| ClinVar | [VCV1130977](https://www.ncbi.nlm.nih.gov/clinvar/variation/1130977/) |

**All HGVS expressions:** `NC_000001.10:g.216462667G>A`, `NC_000001.11:g.216289325G>A`, `NG_009497.2:g.139124C>T`, `NM_007123.6:c.1926C>T`, `NM_206933.4:c.1926C>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 -1, GERP -3.61 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.205**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.27 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00534%** (afr) · FAF95 0.00175% · FAF99 0.00104% · 4/74,926 in the highest group · 6/1,613,860 alleles overall — very rare (popmax 0.00534%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00534% | 18,732 |
| Admixed American | 0.00333% | 30,002 |

*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 **642** lies in the laminin egf-like 3 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.Asp642= falls in the laminin egf-like 3 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-09-11.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2018–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-11 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2018-09-21 |

**Reported phenotype names (ClinVar):** not provided, not specified, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related USH2A variant pages (same residue, condition, or type): [USH2A p.Asp642His](/variant/ush2a-p-asp642his), [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), [USH2A p.Asn346His](/variant/ush2a-p-asn346his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 1130977). 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.*