# NM_004560.4(ROR2):c.1150G>A (p.Val384Ile)

https://sugi.bio/variant/ror2-p-val384ile

## Summary

**ROR2 p.Val384Ile (c.1150G>A)** is classified **Uncertain significance** in ROR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-06). AlphaMissense: likely benign (0.0828); Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · 2 submitters · 3 linked conditions · AlphaMissense likely benign · very rare (popmax 0.0022%, sas)

## 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 2 submitters, and is linked to Inborn genetic diseases.

*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 | [ROR2](https://sugi.bio/atlas/gene/ROR2/) |
| Protein change (HGVS p.) | p.Val384Ile |
| Coding change (HGVS c.) | c.1150G>A |
| MANE Select transcript | [NM_004560](https://www.ncbi.nlm.nih.gov/nuccore/NM_004560) |
| Variant type | single nucleotide variant |
| Location | chr9:91730943-91730943 (GRCh38) |
| ClinVar | [VCV3597755](https://www.ncbi.nlm.nih.gov/clinvar/variation/3597755/) |

**All HGVS expressions:** `NC_000009.11:g.94493225C>T`, `NC_000009.12:g.91730943C>T`, `NG_008089.1:g.224220G>A`, `NM_001318204.2:c.1149+1G>A`, `NM_004560.3:c.1150G>A`, `NM_004560.4:c.1150G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0828)
- REVEL 0.16 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.438 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.69) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.561, GERP -3.84, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.2**. 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 **0.69**, acceptor gain **0.00**, donor gain **0.07**. Largest is donor loss, 1 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.07**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.0022%** (sas) · FAF95 0.0005% · FAF99 0.000366% · 2/91,078 in the highest group · 14/1,614,050 alleles overall — very rare (popmax 0.0022%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0022% | 45,539 |
| African / African-American | 0.00133% | 74,922 |
| European (non-Finnish) | 0.000932% | 107,277 |

*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 **384** lies in the kringle 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.Val384Ile falls in the kringle 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-06.

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

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-06 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-06 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [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):** Inborn genetic diseases, Autosomal recessive Robinow syndrome, Brachydactyly type B1, 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 3597755). 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.*