# NM_206933.4(USH2A):c.13348C>T (p.Pro4450Ser)

https://sugi.bio/variant/ush2a-p-pro4450ser

## Summary

**USH2A p.Pro4450Ser (c.13348C>T)** is classified **Conflicting classifications of pathogenicity** in USH2A (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-06). AlphaMissense: likely pathogenic (0.7568); Ultra-rare (popmax 0.0117%, amr); Associated with USH2A-related disorder.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs141696914 · 5 submitters · 3 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0117%, amr)

## For patients & families {#patients}

This is a change in the USH2A gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, and is linked to USH2A-related disorder.

*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.Pro4450Ser |
| Coding change (HGVS c.) | c.13348C>T |
| MANE Select transcript | [NM_206933](https://www.ncbi.nlm.nih.gov/nuccore/NM_206933) |
| dbSNP | [rs141696914](https://www.ncbi.nlm.nih.gov/snp/rs141696914/) |
| Variant type | single nucleotide variant |
| Location | chr1:215674563-215674563 (GRCh38) |
| ClinVar | [VCV866208](https://www.ncbi.nlm.nih.gov/clinvar/variation/866208/) |

**All HGVS expressions:** `NC_000001.10:g.215847905G>A`, `NC_000001.11:g.215674563G>A`, `NG_009497.2:g.753886C>T`, `NM_206933.3:c.13348C>T`, `NM_206933.4:c.13348C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7568)
- REVEL 0.331 (indeterminate)
- Conservation: phyloP 11.576, GERP 1.79, phastCons 1 — highly conserved (agrees)
- **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.
- AlphaMissense ranks this among the **top 6%** most-pathogenic-predicted substitutions in USH2A (of 30,489 modeled).
- CADD: **PHRED 24.2**. 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: **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 **0.0117%** (amr) · FAF95 0.00543% · FAF99 0.0038% · 7/59,998 in the highest group · 7/1,614,126 alleles overall — ultra-rare (popmax 0.0117%, amr).

*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 **4450** 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.Pro4450Ser 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-06.

**Submitter consensus:** conflicting (2 Uncertain significance, 2 Likely pathogenic, 1 Pathogenic).

**Submission history:** 5 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Myriad Genetics, Inc. | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-16 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-06-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-06 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2018-10-19 |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-29 |

## Associated conditions {#conditions}

[USH2A-related disorder](https://sugi.bio/atlas/disease/ush2a-related-disorder/), [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):** USH2A-related disorder, Usher syndrome type 2A, not provided, Retinitis pigmentosa 39, USH2A-related condition, USH2A-related disorders, RETINAL DISEASE IN USHER SYNDROME TYPE IIA, MODIFIER OF, USHER SYNDROME, TYPE IIA, none provided.

## Same-residue context {#hotspot}

Residue **4450** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [USH2A p.Pro4450Leu](/variant/ush2a-p-pro4450leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related USH2A variant pages (same residue, condition, or type): [USH2A p.Pro4450Leu](/variant/ush2a-p-pro4450leu), [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 2026-10-14); 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 866208). 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.*