# NM_000276.4(OCRL):c.2124C>T (p.Asp708=)

https://sugi.bio/variant/ocrl-p-asp708

## Summary

**OCRL p.Asp708= (c.2124C>T)** is classified **Uncertain significance** in OCRL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-14). Very rare (popmax 0.00173%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1452310953 · 1 submitter · very rare (popmax 0.00173%, afr)

## 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.Asp708= |
| Coding change (HGVS c.) | c.2124C>T |
| MANE Select transcript | [NM_000276](https://www.ncbi.nlm.nih.gov/nuccore/NM_000276) |
| dbSNP | [rs1452310953](https://www.ncbi.nlm.nih.gov/snp/rs1452310953/) |
| Variant type | single nucleotide variant |
| Location | chrX:129584352-129584352 (GRCh38) |
| ClinVar | [VCV1691793](https://www.ncbi.nlm.nih.gov/clinvar/variation/1691793/) |

**All HGVS expressions:** `NC_000023.10:g.128718329C>T`, `NC_000023.11:g.129584352C>T`, `NG_008638.1:g.49078C>T`, `NM_000276.4:c.2124C>T`, `NM_001318784.2:c.2127C>T`, `NM_001587.4:c.2116-2650C>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 **acceptor loss** (Δ 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.606, GERP 2.86, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 11.11**. 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 **0.22**, donor loss **0.18**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.22**, donor loss **0.18**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00173%** (afr) · FAF95 0.00101% · FAF99 0.0008% · 1/57,717 in the highest group · 16/1,208,351 alleles overall — very rare (popmax 0.00173%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00173% | 57,717 |
| European (non-Finnish) | 0.00168% | 59,497 |

*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 2021-12-14.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-12-14 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, 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 1691793). 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.*