# NM_000276.4(OCRL):c.2309_2312del (p.Asp770fs)

https://sugi.bio/variant/ocrl-p-asp770fs

## Summary

**OCRL p.Asp770fs (c.2309_2312del)** is classified **Pathogenic** in OCRL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-29). No gnomAD frequency available for this variant; Associated with oculocerebrorenal syndrome.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs2521945685 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the OCRL gene that is considered disease-causing, submitted by 2 submitters, and is linked to oculocerebrorenal 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.*

|  |  |
| --- | --- |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003295/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [OCRL](https://sugi.bio/atlas/gene/OCRL/) |
| Protein change (HGVS p.) | p.Asp770fs |
| Coding change (HGVS c.) | c.2309_2312del |
| MANE Select transcript | [NM_000276](https://www.ncbi.nlm.nih.gov/nuccore/NM_000276) |
| dbSNP | [rs2521945685](https://www.ncbi.nlm.nih.gov/snp/rs2521945685/) |
| Variant type | Microsatellite |
| Location | chrX:129588227-129588230 (GRCh38) |
| ClinVar | [VCV2747800](https://www.ncbi.nlm.nih.gov/clinvar/variation/2747800/) |

**All HGVS expressions:** `NC_000023.10:g.128722204ATTG[1]`, `NC_000023.11:g.129588227ATTG[1]`, `NG_008638.1:g.52953ATTG[1]`, `NM_000276.3:c.2309_2312del`, `NM_000276.4:c.2309_2312del`, `NM_001318784.2:c.2312_2315del`, `NM_001587.4:c.2285_2288del`

## 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 2.294, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 21 of 24**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**OCRL** population constraint: ClinGen dosage — haploinsufficiency 3/3, 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):

- **oculocerebrorenal syndrome** — Definitive (XL)

## Protein context {#protein}

Residue **770** lies in an α-helix; the rho-gap domain.

AlphaFold model confidence (whole protein): pLDDT 82.91, 60% of residues very-high.

**5 experimental structure(s)** (PDB): [2KIE](https://www.rcsb.org/structure/2KIE), [2QV2](https://www.rcsb.org/structure/2QV2), [3QBT](https://www.rcsb.org/structure/3QBT), [3QIS](https://www.rcsb.org/structure/3QIS), [4CMN](https://www.rcsb.org/structure/4CMN).

## What this gene does {#gene-function}

*Describes the biological roles of OCRL (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:** OCRL's established molecular role includes GTPase activator activity. p.Asp770fs falls in the rho-gap domain.


### Pathways affected {#pathways}

OCRL participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [Golgi Associated Vesicle Biogenesis](https://reactome.org/content/detail/R-HSA-432722) | curated |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | curated |
| [RHOJ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013409) | curated |
| [Synthesis of IP2, IP, and Ins in the cytosol](https://reactome.org/content/detail/R-HSA-1855183) | curated |
| [Synthesis of IP3 and IP4 in the cytosol](https://reactome.org/content/detail/R-HSA-1855204) | curated |
| [Synthesis of PIPs at the Golgi membrane](https://reactome.org/content/detail/R-HSA-1660514) | curated |
| [Synthesis of PIPs at the plasma membrane](https://reactome.org/content/detail/R-HSA-1660499) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** GTPase activator activity, small GTPase binding, inositol phosphate phosphatase activity.

**Biological process:** cilium assembly.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-04-29.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-07 |

## Associated conditions {#conditions}

[oculocerebrorenal syndrome](https://sugi.bio/atlas/disease/oculocerebrorenal-syndrome/).

**Reported phenotype names (ClinVar):** Lowe syndrome, not provided, none provided, LOWE OCULOCEREBRORENAL SYNDROME, PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE 5-PHOSPHATASE DEFICIENCY, Oculocerebrorenal Syndrome.

## Similar variants {#similar}

Related OCRL variant pages (same residue, condition, or type): [OCRL p.Asp480_Ser481insTer](/variant/ocrl-p-asp480-ser481inster), [OCRL p.Ser642fs](/variant/ocrl-p-ser642fs), [OCRL p.Val787fs](/variant/ocrl-p-val787fs), [OCRL p.Leu325del](/variant/ocrl-p-leu325del), [OCRL p.Ile226fs](/variant/ocrl-p-ile226fs), [OCRL p.Leu565fs](/variant/ocrl-p-leu565fs), [OCRL p.Asp770_Cys771insAsp](/variant/ocrl-p-asp770-cys771insasp), [OCRL c.200-4_200-3del](/variant/ocrl-c-200-minus-4-200-minus-3del).

### 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 2747800). 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.*