# NM_004560.4(ROR2):c.1189C>T (p.Arg397Ter)

https://sugi.bio/variant/ror2-p-arg397ter

## Summary

**ROR2 p.Arg397Ter (c.1189C>T)** is classified **Pathogenic** in ROR2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-01-27). Very rare (popmax 0.00439%, sas); Associated with brachydactyly type B1.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1308509155 · 5 submitters · 2 linked conditions · very rare (popmax 0.00439%, sas)

## For patients & families {#patients}

This is a change in the ROR2 gene that is considered disease-causing, submitted by 5 submitters, and is linked to brachydactyly type B1.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018009/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ROR2](https://sugi.bio/atlas/gene/ROR2/) |
| Protein change (HGVS p.) | p.Arg397Ter |
| Coding change (HGVS c.) | c.1189C>T |
| MANE Select transcript | [NM_004560](https://www.ncbi.nlm.nih.gov/nuccore/NM_004560) |
| dbSNP | [rs1308509155](https://www.ncbi.nlm.nih.gov/snp/rs1308509155/) |
| Variant type | single nucleotide variant |
| Location | chr9:91726738-91726738 (GRCh38) |
| ClinVar | [VCV983455](https://www.ncbi.nlm.nih.gov/clinvar/variation/983455/) |

**All HGVS expressions:** `NC_000009.11:g.94489020G>A`, `NC_000009.12:g.91726738G>A`, `NG_008089.1:g.228425C>T`, `NM_001318204.2:c.1155C>T`, `NM_004560.4:c.1189C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 6.341, GERP 1.92, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.543, pLI 0.3497. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 9**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 40.0**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for ROR2 (1,416 scored positions, the nearest 6 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.00439%** (sas) · FAF95 0.00143% · FAF99 0.000891% · 4/91,060 in the highest group · 7/1,613,754 alleles overall — very rare (popmax 0.00439%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00439% | 22,765 |
| East Asian | 0.00223% | 44,880 |
| European (non-Finnish) | 0.000169% | 589,977 |

*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}

**ROR2** population constraint: LOEUF 0.543, pLI 0.3497, missense-Z 1.2805; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 69.09, 23% of residues very-high.

**6 experimental structure(s)** (PDB): [3ZZW](https://www.rcsb.org/structure/3ZZW), [4GT4](https://www.rcsb.org/structure/4GT4), [6OSH](https://www.rcsb.org/structure/6OSH), [6OSN](https://www.rcsb.org/structure/6OSN), [6OSV](https://www.rcsb.org/structure/6OSV), [9FSE](https://www.rcsb.org/structure/9FSE).

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

*Describes the biological roles of ROR2 (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:** ROR2's established molecular role includes Wnt-protein binding.


### Pathways affected {#pathways}

ROR2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [WNT5A-dependent internalization of FZD2, FZD5 and ROR2](https://reactome.org/content/detail/R-HSA-5140745) | curated |
| [PCP/CE pathway](https://reactome.org/content/detail/R-HSA-4086400) | electronic |

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

**Molecular function:** Wnt-protein binding, mitogen-activated protein kinase kinase kinase binding.

**Biological process:** signal transduction, positive regulation of cell migration.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-01-27.

**Submitter consensus:** unanimous (5/5 Pathogenic).

**Submission history:** 5 submissions (2020–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Pathogenic | no assertion criteria provided | research | 2020-04-02 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing |  |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2025-01-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-02-09 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2023-10-01 |

## Associated conditions {#conditions}

[brachydactyly type B1](https://sugi.bio/atlas/disease/brachydactyly-type-b1/), [autosomal recessive Robinow syndrome](https://sugi.bio/atlas/disease/autosomal-recessive-robinow-syndrome/).

**Reported phenotype names (ClinVar):** Brachydactyly type B1, Autosomal recessive Robinow syndrome, not provided, none provided, COSTOVERTEBRAL SEGMENTATION DEFECT WITH MESOMELIA, COVESDEM SYNDROME, ROBINOW SYNDROME, AUTOSOMAL RECESSIVE 1, ROR2-Related Robinow Syndrome.

## Similar variants {#similar}

Related ROR2 variant pages (same residue, condition, or type): [ROR2 c.175+1G>A](/variant/ror2-c-175-plus-1g-a), [ROR2 p.Arg119Ter](/variant/ror2-p-arg119ter), [ROR2 p.Arg442Ter](/variant/ror2-p-arg442ter), [ROR2 p.Arg528Ter](/variant/ror2-p-arg528ter), [ROR2 c.175+3G>T](/variant/ror2-c-175-plus-3g-t), [ROR2 c.-102G>T](/variant/ror2-c-minus-102g-t), [ROR2 c.*135G>T](/variant/ror2-c-star-135g-t), [ROR2 p.Ala413Val](/variant/ror2-p-ala413val).

### 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 983455). 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.*