# NM_006914.4(RORB):c.759G>A (p.Lys253=)

https://sugi.bio/variant/rorb-p-lys253

## Summary

**RORB p.Lys253= (c.759G>A)** is classified **Uncertain significance** in RORB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-20). Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2489621920 · 2 submitters · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the RORB gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters.

*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 | [RORB](https://sugi.bio/atlas/gene/RORB/) |
| Protein change (HGVS p.) | p.Lys253= |
| Coding change (HGVS c.) | c.759G>A |
| MANE Select transcript | [NM_006914](https://www.ncbi.nlm.nih.gov/nuccore/NM_006914) |
| dbSNP | [rs2489621920](https://www.ncbi.nlm.nih.gov/snp/rs2489621920/) |
| Variant type | single nucleotide variant |
| Location | chr9:74660738-74660738 (GRCh38) |
| ClinVar | [VCV2815128](https://www.ncbi.nlm.nih.gov/clinvar/variation/2815128/) |

**All HGVS expressions:** `NC_000009.11:g.77275654G>A`, `NC_000009.12:g.74660738G>A`, `NG_046926.2:g.168403G>A`, `NM_001365023.1:c.792G>A`, `NM_006914.4:c.759G>A`

## 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 loss** (Δ 0.68) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.864, GERP 2.83, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 22.7**. 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 **0.68**, acceptor gain **0.00**, donor gain **0.17**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.68**, acceptor gain **0.00**, donor gain **0.17**.
- Pangolin: Δ**0.79** (loss), gain 0.01 / loss 0.79. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**RORB** population constraint: LOEUF 0.257, pLI 1, missense-Z 3.6678; 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):

- **complex neurodevelopmental disorder** — Definitive (AD)

## Protein context {#protein}

Residue **253** lies in the nr lbd domain; a UniProt-annotated variant site (in eig15; loss of subcellular location in the nucleoplasm).

AlphaFold model confidence (whole protein): pLDDT 79.48, 59% of residues very-high.

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

*Describes the biological roles of RORB (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:** RORB's established molecular role includes sequence-specific double-stranded DNA binding. p.Lys253= falls in the nr lbd domain.


### Pathways affected {#pathways}

RORB participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Nuclear Receptor transcription pathway](https://reactome.org/content/detail/R-HSA-383280) | curated |
| [Expression of BMAL (ARNTL), CLOCK, and NPAS2](https://reactome.org/content/detail/R-HSA-9931509) | electronic |

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

**Molecular function:** sequence-specific double-stranded DNA binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-06-20.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-11-18 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-06-20 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related RORB variant pages (same residue, condition, or type): [RORB c.94-1G>A](/variant/rorb-c-94-minus-1g-a), [RORB p.Arg214Ter](/variant/rorb-p-arg214ter), [RORB p.Arg372Ter](/variant/rorb-p-arg372ter), [RORB p.Arg66Ter](/variant/rorb-p-arg66ter), [RORB p.Ala269Thr](/variant/rorb-p-ala269thr), [RORB p.Ala95Thr](/variant/rorb-p-ala95thr), [RORB p.Arg214Gln](/variant/rorb-p-arg214gln), [RORB p.Arg279Trp](/variant/rorb-p-arg279trp).

### 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 2815128). 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.*