# NM_000276.4(OCRL):c.426_427delinsAC (p.Ser143Pro)

https://sugi.bio/variant/ocrl-p-ser143pro

## Summary

**OCRL p.Ser143Pro (c.426_427delinsAC)** is classified **Uncertain significance** in OCRL (ClinVar, Single submitter, 1 submitter; last evaluated 2015-05-28). No gnomAD frequency available for this variant.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs797045844 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the OCRL gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [OCRL](https://sugi.bio/atlas/gene/OCRL/) |
| Protein change (HGVS p.) | p.Ser143Pro |
| Coding change (HGVS c.) | c.426_427delinsAC |
| MANE Select transcript | [NM_000276](https://www.ncbi.nlm.nih.gov/nuccore/NM_000276) |
| dbSNP | [rs797045844](https://www.ncbi.nlm.nih.gov/snp/rs797045844/) |
| Variant type | Indel |
| Location | chrX:129557937-129557938 (GRCh38) |
| ClinVar | [VCV211781](https://www.ncbi.nlm.nih.gov/clinvar/variation/211781/) |

**All HGVS expressions:** `NC_000023.10:g.128691914_128691915delinsAC`, `NC_000023.11:g.129557937_129557938delinsAC`, `NG_008638.1:g.22663_22664delinsAC`, `NM_000276.4:c.426_427delinsAC`, `NM_001318784.2:c.429_430delinsAC`, `NM_001587.4:c.426_427delinsAC`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 1.612, GERP 0.356, phastCons 0.999 — weakly conserved position
- Regional missense constraint: **o/e 0.99** across the covering region of the MANE Select transcript (129,540,440–129,558,977), spanning 18,537 bp. Chi-square p 0.85. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel 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}


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.


### 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2015-05-28.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Uncertain significance | criteria provided, single submitter | clinical testing | 2015-05-28 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Same-residue context {#hotspot}

Residue **143** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [OCRL p.Ser143fs](/variant/ocrl-p-ser143fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related OCRL variant pages (same residue, condition, or type): [OCRL p.Ser143fs](/variant/ocrl-p-ser143fs), [OCRL p.Ser143Phe](/variant/ocrl-p-ser143phe), [OCRL p.Glu712fs](/variant/ocrl-p-glu712fs), [OCRL p.Leu684fs](/variant/ocrl-p-leu684fs), [OCRL p.Glu806_Leu807delinsAspMet](/variant/ocrl-p-glu806-leu807delinsaspmet), [OCRL c.1244+13_1244+41delinsAAA](/variant/ocrl-c-1244-plus-13-1244-plus-41delinsaaa).

### 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 211781). 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.*