# NM_004560.4(ROR2):c.1347C>G (p.Ser449Arg)

https://sugi.bio/variant/ror2-p-ser449arg

## Summary

**ROR2 p.Ser449Arg (c.1347C>G)** is classified **Uncertain significance** in ROR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely pathogenic (0.9169); Very rare (popmax 0.000124%); Associated with brachydactyly type B1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1837043278 · 1 submitter · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.000124%)

## For patients & families {#patients}

This is a change in the ROR2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Ser449Arg |
| Coding change (HGVS c.) | c.1347C>G |
| MANE Select transcript | [NM_004560](https://www.ncbi.nlm.nih.gov/nuccore/NM_004560) |
| dbSNP | [rs1837043278](https://www.ncbi.nlm.nih.gov/snp/rs1837043278/) |
| Variant type | single nucleotide variant |
| Location | chr9:91726580-91726580 (GRCh38) |
| ClinVar | [VCV914866](https://www.ncbi.nlm.nih.gov/clinvar/variation/914866/) |

**All HGVS expressions:** `NC_000009.11:g.94488862G>C`, `NC_000009.12:g.91726580G>C`, `NG_008089.1:g.228583C>G`, `NM_001318204.2:c.*14C>G`, `NM_004560.4:c.1347C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9169)
- REVEL 0.384 (indeterminate)
- SaProt LLR -7.05 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate
- SpliceAI predicts **donor gain** (Δ 0.68) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.111, GERP 1.77, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.7**. 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.*
- Regional missense constraint: **o/e 0.93** across the covering region of the MANE Select transcript (91,723,665–91,949,963), spanning 226,298 bp. Chi-square p 0.007. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.03**, donor loss **0.10**, acceptor gain **0.00**, donor gain **0.68**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.68**.
- Population frequency (gnomAD v4.1): global (via dbSNP) **0.000124%** · 2/1,613,296 alleles overall — very rare (popmax 0.000124%).

*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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-01-13.

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

**Submission history:** 2 submissions (2018); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |

## 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, COSTOVERTEBRAL SEGMENTATION DEFECT WITH MESOMELIA, COVESDEM SYNDROME, ROR2-Related Robinow Syndrome, ROBINOW SYNDROME, AUTOSOMAL RECESSIVE 1.

## 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.Arg397Ter](/variant/ror2-p-arg397ter), [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).

### 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 914866). 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.*