# NM_004560.4(ROR2):c.79_80del (p.Ser29fs)

https://sugi.bio/variant/ror2-p-ser29fs

## Summary

**ROR2 p.Ser29fs (c.79_80del)** is classified **Pathogenic** in ROR2 (ClinVar, No assertion criteria, 1 submitter). No gnomAD frequency available for this variant; Associated with autosomal recessive Robinow syndrome.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs2118125646 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ROR2 gene that is reported as disease-causing, but on limited review, 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.Ser29fs |
| Coding change (HGVS c.) | c.79_80del |
| MANE Select transcript | [NM_004560](https://www.ncbi.nlm.nih.gov/nuccore/NM_004560) |
| dbSNP | [rs2118125646](https://www.ncbi.nlm.nih.gov/snp/rs2118125646/) |
| Variant type | Microsatellite |
| Location | chr9:91949884-91949885 (GRCh38) |
| ClinVar | [VCV983457](https://www.ncbi.nlm.nih.gov/clinvar/variation/983457/) |

**All HGVS expressions:** `NC_000009.11:g.94712167AG[1]`, `NC_000009.12:g.91949885AG[1]`, `NG_008089.1:g.5276TC[1]`, `NM_001318204.2:c.79_80del`, `NM_004560.4:c.79_80del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -1.191, GERP -1.47 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — 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 1 of 9**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 No assertion criteria *(no assertion criteria provided)*.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Pathogenic | no assertion criteria provided | 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.Ser29Phe](/variant/ror2-p-ser29phe), [ROR2 p.Leu932fs](/variant/ror2-p-leu932fs), [ROR2 c.494+4_494+7del](/variant/ror2-c-494-plus-4-494-plus-7del), [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).

### 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 983457). 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.*