# NM_174878.3(CLRN1):c.384del (p.Phe128fs)

https://sugi.bio/variant/clrn1-p-phe128fs

## Summary

**CLRN1 p.Phe128fs (c.384del)** is classified **Likely pathogenic** in CLRN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-09). Associated with Usher syndrome type 3A.

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

## For patients & families {#patients}

This is a change in the CLRN1 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Usher syndrome type 3A.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015242/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CLRN1](https://sugi.bio/atlas/gene/CLRN1/) |
| Protein change (HGVS p.) | p.Phe128fs |
| Coding change (HGVS c.) | c.384del |
| MANE Select transcript | [NM_174878](https://www.ncbi.nlm.nih.gov/nuccore/NM_174878) |
| Variant type | Deletion |
| Location | chr3:150941631-150941631 (GRCh38) |
| ClinVar | [VCV3601048](https://www.ncbi.nlm.nih.gov/clinvar/variation/3601048/) |

**All HGVS expressions:** `LRG_700:g.36369del`, `LRG_700t1:c.384del`, `LRG_700t2:c.156del`, `NC_000003.11:g.150659421del`, `NC_000003.12:g.150941634del`, `NG_009168.1:g.36369del`, `NM_001195794.1:c.384del`, `NM_001256819.2:c.556del`, `NM_052995.2:c.156del`, `NM_174878.3:c.384del`, `NR_046380.3:n.554del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.675, GERP 1.41, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.168, pLI 8.5957e-05. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **within the last 50 nt of the penultimate exon (2 of 3, 49 nt from its 3' end)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion 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}

**CLRN1** population constraint: LOEUF 1.168, pLI 8.5957e-05, missense-Z -0.36895; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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 3** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 90.74, 77% of residues very-high.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-09.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Rare Diseases, West China Hospital, Sichuan University | Likely pathogenic | criteria provided, single submitter | research | 2025-01-09 |

## Associated conditions {#conditions}

[Usher syndrome type 3A](https://sugi.bio/atlas/disease/usher-syndrome-type-3a/).

**Reported phenotype names (ClinVar):** Usher syndrome type 3A, USHER SYNDROME, TYPE IIIA.

## Similar variants {#similar}

Related CLRN1 variant pages (same residue, condition, or type): [CLRN1 p.Phe193fs](/variant/clrn1-p-phe193fs), [CLRN1 p.Val101fs](/variant/clrn1-p-val101fs), [CLRN1 p.Leu32fs](/variant/clrn1-p-leu32fs), [CLRN1 p.Leu76fs](/variant/clrn1-p-leu76fs), [CLRN1 c.-10_253+10del](/variant/clrn1-c-minus-10-253-plus-10del), [CLRN1 p.Phe124fs](/variant/clrn1-p-phe124fs), [CLRN1 p.Val114fs](/variant/clrn1-p-val114fs), [CLRN1 c.254-2099_254-2086del](/variant/clrn1-c-254-minus-2099-254-minus-2086del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 3601048). 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.*