# NM_000276.4(OCRL):c.1584C>T (p.Ser528=)

https://sugi.bio/variant/ocrl-p-ser528

## Summary

**OCRL p.Ser528= (c.1584C>T)** is classified **Conflicting classifications of pathogenicity** in OCRL (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-05). Ultra-rare (popmax 0.0218%, amr); Associated with oculocerebrorenal syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs762009796 · 4 submitters · 1 linked condition · ultra-rare (popmax 0.0218%, amr)

## For patients & families {#patients}

This is a change in the OCRL gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 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.Ser528= |
| Coding change (HGVS c.) | c.1584C>T |
| MANE Select transcript | [NM_000276](https://www.ncbi.nlm.nih.gov/nuccore/NM_000276) |
| dbSNP | [rs762009796](https://www.ncbi.nlm.nih.gov/snp/rs762009796/) |
| Variant type | single nucleotide variant |
| Location | chrX:129569381-129569381 (GRCh38) |
| ClinVar | [VCV2797589](https://www.ncbi.nlm.nih.gov/clinvar/variation/2797589/) |

**All HGVS expressions:** `NC_000023.10:g.128703358C>T`, `NC_000023.11:g.129569381C>T`, `NG_008638.1:g.34107C>T`, `NM_000276.3:c.1584C>T`, `NM_000276.4:c.1584C>T`, `NM_001318784.2:c.1587C>T`, `NM_001587.4:c.1584C>T`

## Computational & population evidence {#evidence}

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

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.57) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.513, GERP -2.21, phastCons 0.03 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 18.2**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.02**, acceptor gain **0.00**, donor gain **0.57**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.02**, acceptor gain **0.00**, donor gain **0.57**.
- Pangolin: Δ**0.22** (gain), gain 0.22 / loss 0.06. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0218%** (amr) · FAF95 0.0118% · FAF99 0.009% · 10/45,794 in the highest group · 58/1,209,081 alleles overall — ultra-rare (popmax 0.0218%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0772% | 1,295 |
| Admixed American (grpmax) | 0.0218% | 4,579 |
| East Asian | 0.00888% | 11,260 |
| Remaining individuals (not grpmax-eligible) | 0.00841% | 11,891 |
| South Asian | 0.00176% | 56,836 |
| European (non-Finnish) | 0.000447% | 223,565 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **528** lies in a β-strand; the 5-ppase 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.Ser528= falls in the 5-ppase 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-05.

**Submitter consensus:** conflicting (3 Likely benign, 1 Uncertain significance).

**Submission history:** 4 submissions (2021–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-31 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-05 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-05-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-12-29 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related OCRL variant pages (same residue, condition, or type): [OCRL c.1244+1G>A](/variant/ocrl-c-1244-plus-1g-a), [OCRL c.1714-1G>A](/variant/ocrl-c-1714-minus-1g-a), [OCRL c.2256+1G>T](/variant/ocrl-c-2256-plus-1g-t), [OCRL c.560+1G>C](/variant/ocrl-c-560-plus-1g-c), [OCRL c.940-11G>A](/variant/ocrl-c-940-minus-11g-a), [OCRL p.Ala861Thr](/variant/ocrl-p-ala861thr), [OCRL p.Arg318Cys](/variant/ocrl-p-arg318cys), [OCRL p.Arg318His](/variant/ocrl-p-arg318his).

### 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 2797589). 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.*