# NM_174878.3(CLRN1):c.165del (p.Asp55fs)

https://sugi.bio/variant/clrn1-p-asp55fs

## Summary

**CLRN1 p.Asp55fs (c.165del)** is classified **Likely pathogenic** in CLRN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-15). Very rare (popmax 8.47e-05%, nfe); Associated with CLRN1-related disorder.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1235835151 · 1 submitter · 1 linked condition · very rare (popmax 8.47e-05%, nfe)

## 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 CLRN1-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 | [CLRN1](https://sugi.bio/atlas/gene/CLRN1/) |
| Protein change (HGVS p.) | p.Asp55fs |
| Coding change (HGVS c.) | c.165del |
| MANE Select transcript | [NM_174878](https://www.ncbi.nlm.nih.gov/nuccore/NM_174878) |
| dbSNP | [rs1235835151](https://www.ncbi.nlm.nih.gov/snp/rs1235835151/) |
| Variant type | Deletion |
| Location | chr3:150972544-150972544 (GRCh38) |
| ClinVar | [VCV866927](https://www.ncbi.nlm.nih.gov/clinvar/variation/866927/) |

**All HGVS expressions:** `LRG_700:g.5456del`, `LRG_700t1:c.165del`, `NC_000003.11:g.150690331del`, `NC_000003.12:g.150972544del`, `NG_009168.1:g.5456del`, `NM_001195794.1:c.165del`, `NM_001256819.2:c.165del`, `NM_174878.3:c.165del`, `NR_046380.3:n.184del`

## 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 5.114, GERP 1.68, 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 **in exon 1 of 3**, so the transcript is predicted to undergo NMD.
- 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.
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,038 in the highest group · 1/1,614,188 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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 gene assoc. with recessive phenotype, triplosensitivity 0/3. *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 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 2021-03-15.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-03-15 |

## Associated conditions {#conditions}

[CLRN1-related disorder](https://sugi.bio/atlas/disease/clrn1-related-disorder/).

**Reported phenotype names (ClinVar):** CLRN1-related disorder, CLRN1-related condition.

## Similar variants {#similar}

Related CLRN1 variant pages (same residue, condition, or type): [CLRN1 p.Asp55Glu](/variant/clrn1-p-asp55glu), [CLRN1 c.254-2A>G](/variant/clrn1-c-254-minus-2a-g), [CLRN1 c.254-649T>G](/variant/clrn1-c-254-minus-649t-g), [CLRN1 c.433+1G>A](/variant/clrn1-c-433-plus-1g-a), [CLRN1 p.Ala123Asp](/variant/clrn1-p-ala123asp), [CLRN1 p.Arg207Ter](/variant/clrn1-p-arg207ter), [CLRN1 p.Gln52Ter](/variant/clrn1-p-gln52ter), [CLRN1 p.Ile168fs](/variant/clrn1-p-ile168fs).

### 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 866927). 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.*