# NM_004560.4(ROR2):c.854A>G (p.Lys285Arg)

https://sugi.bio/variant/ror2-p-lys285arg

## Summary

**ROR2 p.Lys285Arg (c.854A>G)** is classified **Likely pathogenic** in ROR2 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.0704); Ultra-rare (popmax 0.0264%, sas); Associated with autosomal recessive Robinow syndrome.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs768848657 · 1 submitter · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0264%, sas)

## For patients & families {#patients}

This is a change in the ROR2 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to autosomal recessive Robinow 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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016568/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.Lys285Arg |
| Coding change (HGVS c.) | c.854A>G |
| MANE Select transcript | [NM_004560](https://www.ncbi.nlm.nih.gov/nuccore/NM_004560) |
| dbSNP | [rs768848657](https://www.ncbi.nlm.nih.gov/snp/rs768848657/) |
| Variant type | single nucleotide variant |
| Location | chr9:91733205-91733205 (GRCh38) |
| ClinVar | [VCV2502303](https://www.ncbi.nlm.nih.gov/clinvar/variation/2502303/) |

**All HGVS expressions:** `NC_000009.11:g.94495487T>C`, `NC_000009.12:g.91733205T>C`, `NG_008089.1:g.221958A>G`, `NM_001318204.2:c.854A>G`, `NM_004560.4:c.854A>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.0704) — ⚠ discordant with the pathogenic call
- REVEL 0.238 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.404 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.29) — consistent with the pathogenic call
- Conservation: phyloP 2.766, GERP 1.88, phastCons 0.999 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.3**. 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 **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.29**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.29**.
- Population frequency (gnomAD v4.1): grpmax **0.0264%** (sas) · FAF95 0.0181% · FAF99 0.0155% · 24/90,746 in the highest group · 24/1,611,664 alleles overall — ultra-rare (popmax 0.0264%, sas).

*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}

Residue **285** lies in the fz domain.

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. p.Lys285Arg falls in the fz domain.


### 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Division of Medical Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi | Likely pathogenic | criteria provided, single submitter | research |  |

## Associated conditions {#conditions}

[autosomal recessive Robinow syndrome](https://sugi.bio/atlas/disease/autosomal-recessive-robinow-syndrome/).

**Reported phenotype names (ClinVar):** Autosomal recessive Robinow syndrome, ROR2-Related Robinow Syndrome, COSTOVERTEBRAL SEGMENTATION DEFECT WITH MESOMELIA, COVESDEM SYNDROME, ROBINOW SYNDROME, AUTOSOMAL RECESSIVE 1.

## Similar variants {#similar}

Related ROR2 variant pages (same residue, condition, or type): [ROR2 p.Lys285Glu](/variant/ror2-p-lys285glu), [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).

### 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 2502303). 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.*