# NM_005012.4(ROR1):c.1353A>G (p.Val451=)

https://sugi.bio/variant/ror1-p-val451

## Summary

**ROR1 p.Val451= (c.1353A>G)** is classified **Benign** in ROR1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). Common (popmax 43.4%, eas) — too common for a highly-penetrant pathogenic allele; Associated with hearing loss, autosomal recessive 108.

**At a glance:** Benign · review: Multiple submitters · rsID rs6668545 · 4 submitters · 1 linked condition · common (popmax 43.4%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the ROR1 gene that is classified as benign — not considered disease-causing, submitted by 4 submitters, and is linked to hearing loss, autosomal recessive 108.

*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/0022658/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ROR1](https://sugi.bio/atlas/gene/ROR1/) |
| Protein change (HGVS p.) | p.Val451= |
| Coding change (HGVS c.) | c.1353A>G |
| MANE Select transcript | [NM_005012](https://www.ncbi.nlm.nih.gov/nuccore/NM_005012) |
| dbSNP | [rs6668545](https://www.ncbi.nlm.nih.gov/snp/rs6668545/) |
| Variant type | single nucleotide variant |
| Location | chr1:64159159-64159159 (GRCh38) |
| ClinVar | [VCV1260721](https://www.ncbi.nlm.nih.gov/clinvar/variation/1260721/) |

**All HGVS expressions:** `NC_000001.10:g.64624842A>G`, `NC_000001.11:g.64159159A>G`, `NG_032801.2:g.390141A>G`, `NM_005012.4:c.1353A>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 43.4%, eas) — too common for a highly-penetrant pathogenic allele.

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.25) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -1.425, GERP -5.11 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.188**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.25**. Largest is donor gain, 33 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  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 **43.4%** (eas) · FAF95 42.9% · FAF99 42.6% · 19,454/44,860 in the highest group · 573,355/1,613,362 alleles overall — common (popmax 43.4%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 43.4% | 2 |
| Middle Eastern | 39.3% | 3 |
| South Asian | 38.8% | 3 |
| Admixed American | 37.8% | 3 |
| Remaining individuals (not grpmax-eligible) | 36.4% | 3 |
| Finnish (not grpmax-eligible) | 36.2% | 3 |
| Ashkenazi Jewish (not grpmax-eligible) | 35.8% | 3 |
| European (non-Finnish) | 35.6% | 3 |
| Amish (not grpmax-eligible) | 26.4% | 4 |
| African / African-American | 22.8% | 4 |

*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}

**ROR1** population constraint: LOEUF 0.326, pLI 1, missense-Z 3.1497. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **nonsyndromic genetic hearing loss** — Limited (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 69.17, 26% of residues very-high.

**5 experimental structure(s)** (PDB): [5Z55](https://www.rcsb.org/structure/5Z55), [6BA5](https://www.rcsb.org/structure/6BA5), [6BAN](https://www.rcsb.org/structure/6BAN), [6TU9](https://www.rcsb.org/structure/6TU9), [7TNG](https://www.rcsb.org/structure/7TNG).

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

*Describes the biological roles of ROR1 (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:** ROR1's established molecular role includes Wnt-protein binding.


### Pathways affected {#pathways}

ROR1 participates in **1 Reactome pathway** (⚕ = disease pathway):

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

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

**Molecular function:** Wnt-protein binding, signaling receptor activity, Wnt receptor activity.

**Biological process:** sensory perception of sound, cell population proliferation, positive regulation of canonical NF-kappaB signal transduction.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-03.

**Submitter consensus:** unanimous (4/4 Benign).

**Submission history:** 4 submissions (2021–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2021-05-04 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-11-07 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-03 |

## Associated conditions {#conditions}

[hearing loss, autosomal recessive 108](https://sugi.bio/atlas/disease/hearing-loss-autosomal-recessive-108/).

**Reported phenotype names (ClinVar):** Hearing loss, autosomal recessive 108, not provided, DEAFNESS, AUTOSOMAL RECESSIVE 108, none provided.

## Similar variants {#similar}

Related ROR1 variant pages (same residue, condition, or type): [ROR1 p.Pro547Ser](/variant/ror1-p-pro547ser), [ROR1 p.Ala390=](/variant/ror1-p-ala390), [ROR1 p.Leu60=](/variant/ror1-p-leu60), [ROR1 p.Thr518Met](/variant/ror1-p-thr518met), [ROR1 p.Glu452Asp](/variant/ror1-p-glu452asp), [ROR1 p.Tyr910Asp](/variant/ror1-p-tyr910asp), [ROR1 p.Ala596Ser](/variant/ror1-p-ala596ser), [ROR1 p.Ala833Ser](/variant/ror1-p-ala833ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 1260721). 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.*