# NM_000276.4(OCRL):c.430G>T (p.Val144Phe)

https://sugi.bio/variant/ocrl-p-val144phe

## Summary

**OCRL p.Val144Phe (c.430G>T)** is classified **Uncertain significance** in OCRL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-02). AlphaMissense: likely benign (0.0781); Very rare (popmax 0.00297%, eas); Associated with oculocerebrorenal syndrome.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1283513096 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00297%, eas)

## 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, 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.Val144Phe |
| Coding change (HGVS c.) | c.430G>T |
| MANE Select transcript | [NM_000276](https://www.ncbi.nlm.nih.gov/nuccore/NM_000276) |
| dbSNP | [rs1283513096](https://www.ncbi.nlm.nih.gov/snp/rs1283513096/) |
| Variant type | single nucleotide variant |
| Location | chrX:129557941-129557941 (GRCh38) |
| ClinVar | [VCV1394607](https://www.ncbi.nlm.nih.gov/clinvar/variation/1394607/) |

**All HGVS expressions:** `NC_000023.10:g.128691918G>T`, `NC_000023.11:g.129557941G>T`, `NG_008638.1:g.22667G>T`, `NM_000276.4:c.430G>T`, `NM_001318784.2:c.433G>T`, `NM_001587.4:c.430G>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0781)
- REVEL 0.234 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.813 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.312, GERP 1.85, phastCons 0.965 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 11.98**. 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.*
- 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Pangolin: Δ**0.26** (loss), gain 0.01 / loss 0.26. Not in the SpliceAI release. 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 **0.00297%** (eas) · 1/33,686 in the highest group · 1/1,170,135 alleles overall — very rare (popmax 0.00297%, eas).

*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 2021-12-02.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-12-02 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Lowe syndrome, 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.Val144=](/variant/ocrl-p-val144), [OCRL p.Val144Ala](/variant/ocrl-p-val144ala), [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).

### 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 1394607). 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.*