# NM_206933.4(USH2A):c.13396C>T (p.Pro4466Ser)

https://sugi.bio/variant/ush2a-p-pro4466ser

## Summary

**USH2A p.Pro4466Ser (c.13396C>T)** is classified **Uncertain significance** in USH2A (ClinVar, Expert panel, 11 submitters; last evaluated 2022-11-22). AlphaMissense: likely benign (0.1079); Ultra-rare (popmax 0.0435%, nfe); Associated with Usher syndrome.

**At a glance:** Uncertain significance · review: Expert panel · rsID rs138398671 · 11 submitters · 4 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0435%, nfe)

## For patients & families {#patients}

This is a change in the USH2A gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 11 submitters, and is linked to Usher syndrome.

*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 recessive |
| Age of onset (of this condition) | Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Worldwide) |
| Clinical trials | 19 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | USH2A is a diagnostic-grade gene on 3 Genomics England panels |

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

- Sensorineural hearing impairment — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Abnormal electroretinogram — Very frequent (99-80%)
- Progressive visual loss — Very frequent (99-80%)
- Blindness — Very frequent (99-80%)
- Nyctalopia — Very frequent (99-80%)
- Visual field defect — Very frequent (99-80%)
- Abnormal vestibular function — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007843/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.Pro4466Ser |
| Coding change (HGVS c.) | c.13396C>T |
| MANE Select transcript | [NM_206933](https://www.ncbi.nlm.nih.gov/nuccore/NM_206933) |
| dbSNP | [rs138398671](https://www.ncbi.nlm.nih.gov/snp/rs138398671/) |
| Variant type | single nucleotide variant |
| Location | chr1:215674515-215674515 (GRCh38) |
| ClinVar | [VCV48417](https://www.ncbi.nlm.nih.gov/clinvar/variation/48417/) |

**All HGVS expressions:** `NC_000001.10:g.215847857G>A`, `NC_000001.11:g.215674515G>A`, `NG_009497.2:g.753934C>T`, `NM_206933.4:c.13396C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1079)
- REVEL 0.049 (moderately benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- Conservation: phyloP 3.048, GERP 0.747, phastCons 0.999 — highly conserved (differs from AlphaMissense)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- CADD: **PHRED 16.75**. 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 1.05** across the covering region of the MANE Select transcript (215,625,784–216,422,336), spanning 796,552 bp. Chi-square p 0.00011. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for USH2A (5,179 scored positions, the nearest 24 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.0435%** (nfe) · FAF95 0.0403% · FAF99 0.0391% · 513/1,180,020 in the highest group · 538/1,614,044 alleles overall — ultra-rare (popmax 0.0435%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0435% | 2,300 |
| Remaining individuals (not grpmax-eligible) | 0.0176% | 5,681 |
| Admixed American | 0.00833% | 12,002 |
| Finnish (not grpmax-eligible) | 0.00781% | 12,806 |
| African / African-American | 0.004% | 24,974 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,608 |

*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 **4466** lies in the fibronectin type-iii 30 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.Pro4466Ser falls in the fibronectin type-iii 30 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}

**Uncertain significance** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2022-11-22.

**Submitter consensus:** conflicting (8 Uncertain significance, 1 Uncertain Significance, 1 Likely pathogenic, 1 Likely benign).

**Submission history:** 11 submissions (2015–2025); classifications have differed over time.

**ClinGen expert panel:** Uncertain Significance — Hearing Loss VCEP (Usher syndrome). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM3_Supporting`, `BP4`.
*Considered but not met:* `PM6`, `PM2_supporting`, `PVS1`, `PS1`, `PS2`, `PS3`, `PS4`, `PM1`, `PP1`, `PP2`, `PP3`, `PP4`, `BS2`, `BS1`, `BS4`, `BS3`, `BP5`, `BP7`, `PM5`, `BP3`, `BP1`, `BP2`, `BA1`, `PM4`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The variant NM_206933.4:c.13396C>T in USH2A is a missense variant predicted to cause substitution of proline by serine at amino acid 4466 (p.Pro4466Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00044 (57/128120 alleles) in the European (non-Finnish) population, which does not meet either PM2_supporting nor BS1 criteria. The REVEL computational prediction analysis tool produced a score of 0.049, which is below the threshold necessary to apply BP4. This variant has been reported in two probands, one with retinitis pigmentosa, however the second variant was not specified and no PM3 points were awarded and the other homozygous with inherited retinal disease (PM3_Supporting; PMID 28041643, 32581362). In summary, the variant meets criteria to be classified as uncertain significance for AR Usher syndrome. ACMG/AMP criteria met, as specified by the ClinGen Hearing Loss VCEP: BP4, PM3_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 11/22/2022)
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50007 · approved 2022-11-22 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/afedcdf5-4814-4f0e-a431-fb76cffe27e8).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2019-11-06 |
| ClinGen Hearing Loss Variant Curation Expert Panel | Uncertain significance | reviewed by expert panel | curation | 2022-11-22 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Uncertain Significance | criteria provided, single submitter | clinical testing | 2021-07-14 |
| NIHR Bioresource Rare Diseases, University of Cambridge | Likely pathogenic | no assertion criteria provided | research | 2015-01-01 |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2018-03-30 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-04 |
| Breakthrough Genomics, Breakthrough Genomics | Uncertain significance | criteria provided, single submitter | not provided |  |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-11 |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-09-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-11 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Usher syndrome, Retinitis pigmentosa, Retinitis pigmentosa 39, Usher syndrome type 2A, not provided, USH2A-related disorder, not specified, Usher Syndromes, Usher's syndrome, USH2A-related condition.

## Similar variants {#similar}

Related USH2A variant pages (same residue, condition, or type): [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), [USH2A p.Asn4292Asp](/variant/ush2a-p-asn4292asp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 48417). 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.*