# NM_002335.4(LRP5):c.2046T>C (p.Phe682=)

https://sugi.bio/variant/lrp5-p-phe682

## Summary

**LRP5 p.Phe682= (c.2046T>C)** is classified **Conflicting classifications of pathogenicity** in LRP5 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-11). Rare (popmax 0.143%, afr); Associated with exudative vitreoretinopathy 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs61740517 · 5 submitters · 8 linked conditions · rare (popmax 0.143%, afr)

## For patients & families {#patients}

This is a change in the LRP5 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, and is linked to exudative vitreoretinopathy 1.

*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/0015068/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [LRP5](https://sugi.bio/atlas/gene/LRP5/) |
| Protein change (HGVS p.) | p.Phe682= |
| Coding change (HGVS c.) | c.2046T>C |
| MANE Select transcript | [NM_002335](https://www.ncbi.nlm.nih.gov/nuccore/NM_002335) |
| dbSNP | [rs61740517](https://www.ncbi.nlm.nih.gov/snp/rs61740517/) |
| Variant type | single nucleotide variant |
| Location | chr11:68406768-68406768 (GRCh38) |
| ClinVar | [VCV1096346](https://www.ncbi.nlm.nih.gov/clinvar/variation/1096346/) |

**All HGVS expressions:** `NC_000011.10:g.68406768T>C`, `NC_000011.9:g.68174236T>C`, `NG_015835.2:g.99129T>C`, `NM_001291902.2:c.303T>C`, `NM_002335.4:c.2046T>C`

## 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 -11.619, GERP -3.58 — fast-evolving / accelerated position
- CADD: **PHRED 0.225**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.143%** (afr) · FAF95 0.121% · FAF99 0.112% · 107/75,036 in the highest group · 123/1,614,118 alleles overall — rare (popmax 0.143%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.143% | 701 |
| Remaining individuals (not grpmax-eligible) | 0.0144% | 6,946 |
| Admixed American | 0.01% | 10,004 |
| South Asian | 0.0011% | 91,078 |

*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}

**LRP5** population constraint: LOEUF 0.482, pLI 0.9406, missense-Z 3.7149; ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **LRP5-related exudative vitreoretinopathy** — Definitive (AR)
- **polycystic liver disease 4 with or without kidney cysts** — Limited (AD)

## Protein context {#protein}

Residue **682** lies in the 'beta-propeller 3' region.

AlphaFold model confidence (whole protein): pLDDT 78.65, 42% of residues very-high.

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

*Describes the biological roles of LRP5 (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:** LRP5's established molecular role includes coreceptor activity. p.Phe682= falls in the beta-propeller 3 region. In Reactome, LRP5 is annotated in disease pathway(s) including **Signaling by LRP5 mutants **, **Signaling by RNF43 mutants**.

**Disease mechanism (Reactome):** LRP5 loss or alteration is curated in [Signaling by LRP5 mutants ](https://reactome.org/content/detail/R-HSA-5339717), [Signaling by RNF43 mutants](https://reactome.org/content/detail/R-HSA-5340588).

### Pathways affected {#pathways}

LRP5 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Signaling by LRP5 mutants ](https://reactome.org/content/detail/R-HSA-5339717) | curated |
| ⚕ [Signaling by RNF43 mutants](https://reactome.org/content/detail/R-HSA-5340588) | curated |
| [Negative regulation of TCF-dependent signaling by WNT ligand antagonists](https://reactome.org/content/detail/R-HSA-3772470) | curated |
| [Regulation of FZD by ubiquitination](https://reactome.org/content/detail/R-HSA-4641263) | curated |
| [Disassembly of the destruction complex and recruitment of AXIN to the membrane](https://reactome.org/content/detail/R-HSA-4641262) | electronic |
| [TCF dependent signaling in response to WNT](https://reactome.org/content/detail/R-HSA-201681) | electronic |

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

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

**Biological process:** positive regulation of mesenchymal cell proliferation, glucose catabolic process, regulation of blood pressure, positive regulation of cell population proliferation, cholesterol homeostasis, positive regulation of fat cell differentiation.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-11.

**Submitter consensus:** conflicting (4 Likely benign, 1 Uncertain significance).

**Submission history:** 5 submissions (2021–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-01-28 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-10-15 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2024-09-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-11 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-11-05 |

## Associated conditions {#conditions}

[exudative vitreoretinopathy 1](https://sugi.bio/atlas/disease/exudative-vitreoretinopathy-1/), [osteoporosis](https://sugi.bio/atlas/disease/osteoporosis/), [autosomal dominant osteosclerosis, Worth type](https://sugi.bio/atlas/disease/autosomal-dominant-osteosclerosis-worth-type/), [osteoporosis-pseudoglioma syndrome](https://sugi.bio/atlas/disease/osteoporosis-pseudoglioma-syndrome/), [exudative vitreoretinopathy 4](https://sugi.bio/atlas/disease/exudative-vitreoretinopathy-4/), [autosomal dominant osteopetrosis 1](https://sugi.bio/atlas/disease/autosomal-dominant-osteopetrosis-1/), [osteogenesis imperfecta](https://sugi.bio/atlas/disease/osteogenesis-imperfecta/), [polycystic liver disease 4 with or without kidney cysts](https://sugi.bio/atlas/disease/polycystic-liver-disease-4-with-or-without-kidney-cysts/).

**Reported phenotype names (ClinVar):** Exudative vitreoretinopathy 1, not provided, Osteogenesis imperfecta, Autosomal dominant osteopetrosis 1, Bone mineral density quantitative trait locus 1, Exudative vitreoretinopathy 4, Osteoporosis, Osteoporosis with pseudoglioma, Polycystic liver disease 4 with or without kidney cysts, Worth disease.

## Similar variants {#similar}

Related LRP5 variant pages (same residue, condition, or type): [LRP5 c.1412+1G>A](/variant/lrp5-c-1412-plus-1g-a), [LRP5 c.3236+2T>G](/variant/lrp5-c-3236-plus-2t-g), [LRP5 c.4488+2T>G](/variant/lrp5-c-4488-plus-2t-g), [LRP5 c.884-2A>G](/variant/lrp5-c-884-minus-2a-g), [LRP5 p.Ala214Thr](/variant/lrp5-p-ala214thr), [LRP5 p.Ala242Thr](/variant/lrp5-p-ala242thr), [LRP5 p.Ala422Thr](/variant/lrp5-p-ala422thr), [LRP5 p.Arg1078Ter](/variant/lrp5-p-arg1078ter).

### 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 1096346). 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.*