# NM_000527.5(LDLR):c.542C>G (p.Pro181Arg)

https://sugi.bio/variant/ldlr-p-pro181arg

## Summary

**LDLR p.Pro181Arg (c.542C>G)** is classified **Likely pathogenic** in LDLR (ClinVar, Expert panel, 25 submitters; last evaluated 2024-02-23). AlphaMissense: likely benign (0.1714); Very rare (popmax 0.00161%, nfe); Associated with hypercholesterolemia, familial, 1.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs557344672 · 25 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00161%, nfe)

## For patients & families {#patients}

This is a change in the LDLR gene that is considered likely disease-causing, submitted by 25 submitters, and is linked to hypercholesterolemia, familial, 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.*

|  |  |
| --- | --- |
| Clinical trials | 28 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024574/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [LDLR](https://sugi.bio/atlas/gene/LDLR/) |
| Protein change (HGVS p.) | p.Pro181Arg |
| Coding change (HGVS c.) | c.542C>G |
| MANE Select transcript | [NM_000527](https://www.ncbi.nlm.nih.gov/nuccore/NM_000527) |
| dbSNP | [rs557344672](https://www.ncbi.nlm.nih.gov/snp/rs557344672/) |
| Variant type | single nucleotide variant |
| Location | chr19:11105448-11105448 (GRCh38) |
| ClinVar | [VCV183089](https://www.ncbi.nlm.nih.gov/clinvar/variation/183089/) |

**All HGVS expressions:** `LRG_274:g.21068C>G`, `LRG_274t1:c.542C>G`, `NC_000019.10:g.11105448C>G`, `NC_000019.9:g.11216124C>G`, `NG_009060.1:g.21068C>G`, `NM_000527.5:c.542C>G`, `NM_001195798.2:c.542C>G`, `NM_001195799.2:c.419C>G`, `NM_001195800.2:c.314-1944C>G`, `NM_001195803.2:c.314-1117C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1714) — ⚠ discordant with the pathogenic call
- REVEL 0.713 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -5.784 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 1.194, GERP -0.842, phastCons 0.666 — weakly conserved position
- 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 1.00** across the covering region of the MANE Select transcript (11,089,549–11,131,313), spanning 41,764 bp. Chi-square p 0.91. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.00161%** (nfe) · FAF95 0.00103% · FAF99 0.00083% · 19/1,180,042 in the highest group · 20/1,613,924 alleles overall — very rare (popmax 0.00161%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00161% | 62,108 |
| African / African-American | 0.00133% | 74,932 |

*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}

**LDLR** population constraint: LOEUF 1.091, pLI 1.2477e-30, missense-Z 0.60522; ClinGen dosage — haploinsufficiency 3/3, 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):

- **hypercholesterolemia, familial, 1** — Definitive (SD)

## Protein context {#protein}

Residue **181** lies in the 'binding to getah virus e1-e2 spike glycoproteins' region; an α-helix; the ldl-receptor class a 4 domain.

AlphaFold model confidence (whole protein): pLDDT 75.81, 29% of residues very-high.

**36 experimental structure(s)** (PDB): [1AJJ](https://www.rcsb.org/structure/1AJJ), [1D2J](https://www.rcsb.org/structure/1D2J), [1F5Y](https://www.rcsb.org/structure/1F5Y), [1F8Z](https://www.rcsb.org/structure/1F8Z), [1HJ7](https://www.rcsb.org/structure/1HJ7), [1HZ8](https://www.rcsb.org/structure/1HZ8) — incl. mutant structure 2W2N.

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

*Describes the biological roles of LDLR (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:** LDLR's established molecular role includes protease binding. p.Pro181Arg falls in the binding to getah virus e1-e2 spike glycoproteins region.


### Pathways affected {#pathways}

LDLR participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cargo recognition for clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856825) | curated |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [LDL clearance](https://reactome.org/content/detail/R-HSA-8964038) | curated |
| [Chylomicron clearance](https://reactome.org/content/detail/R-HSA-8964026) | electronic |
| [Retinoid metabolism and transport](https://reactome.org/content/detail/R-HSA-975634) | electronic |

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

**Molecular function:** protease binding, low-density lipoprotein particle receptor activity, low-density lipoprotein particle binding, very-low-density lipoprotein particle receptor activity, identical protein binding, molecular adaptor activity.

**Biological process:** negative regulation of receptor recycling, long-term memory, negative regulation of low-density lipoprotein particle clearance, intestinal cholesterol absorption, cholesterol transport, low-density lipoprotein particle clearance.

## Clinical significance {#significance}

**Likely pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2024-02-23.

**Submitter consensus:** conflicting (14 Likely pathogenic, 4 Uncertain significance, 2 Pathogenic, 2 Likely Pathogenic, 1 not provided, 1 likely pathogenic, 1 Likely benign).

**Submission history:** 23 submissions (2016–2026); classifications have differed over time.

**ClinGen expert panel:** Likely Pathogenic — Familial Hypercholesterolemia VCEP (hypercholesterolemia, familial). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2`, `PS3_Moderate`, `PS4_Moderate`, `PM1`, `PP4`.
*Considered but not met:* `PM6`, `PVS1`, `PS1`, `PS2`, `PP1`, `PP3`, `BS2`, `PM3`, `BS1`, `BS4`, `BS3`, `PM5`, `BP4`, `BP3`, `BP2`, `BA1`, `PM4`.
Inheritance: Semidominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000527.5(LDLR):c.542C>G (p.Pro181Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PS3_Moderate, PS4_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024.  The supporting evidence is as follows:  PM2: PopMax MAF = 0.00005 (0.005%) in European (Non-Finnish) exomes+genomes (gnomAD v4.0.0).  PM1: Variant meets PM2 and is a missense in exon 4.  PS3_Moderate: Level 2 assay: PMID 21868016 (Garcia-Garcia A et al., 2011): COS-7 cells. Mature/precursor LDLR forms ratio ~60% ---- Overall LDLR biosynthesis is below 70% of wild-type activity.  PS4_Moderate, PP4: Variant meets PM2 and is identified in at least 6 unrelated index cases who fulfill criteria for FH (1 case from PMID 16250003 (Fouchier SW et al., 2005); 2 cases with MedPed and Simon Broome criteria from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic, and PMID 22698793 (Tichý L et al., 2012); 2 cases meeting Simon Broome and DLCN criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 1 case with DLCN score>=6 from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50004 · approved 2024-02-23 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/c2e8a4a2-bae2-4d81-aa9a-f795650a42fa).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-03-20 |
| U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Likely pathogenic | criteria provided, single submitter | clinical testing | 2017-03-30 |
| Institute of Human Genetics, Heidelberg University | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-12-09 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-06-03 |
| Dept. of Genetics and Pharmacogenomics, Merck Research Labs | not provided | no classification provided | in vitro |  |
| Quest Diagnostics Nichols Institute San Juan Capistrano | likely pathogenic | criteria provided, single submitter | clinical testing | 2025-04-01 |
| Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix | Likely benign | flagged submission | clinical testing | 2016-12-16 |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | Pathogenic | no assertion criteria provided | research |  |
| Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Uncertain significance | no assertion criteria provided | clinical testing | 2023-10-09 |
| All of Us Research Program, National Institutes of Health | Likely Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-26 |
| Ambry Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-11-18 |
| Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-11-05 |
| Institute of Human Genetics, University of Leipzig Medical Center | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-09-10 |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-24 |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-11-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-01 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-06-04 |
| LDLR-LOVD, British Heart Foundation | Likely pathogenic | criteria provided, single submitter | literature only | 2016-03-25 |
| Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Likely pathogenic | criteria provided, single submitter | clinical testing | 2018-04-25 |
| Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-05-24 |
| ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Likely Pathogenic | reviewed by expert panel | curation | 2024-02-23 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-06-03 |
| Institute of Human Genetics Munich, TUM University Hospital | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-10-31 |
| Color Diagnostics, LLC DBA Color Health | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-06-23 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-24 |

## Associated conditions {#conditions}

[hypercholesterolemia, familial, 1](https://sugi.bio/atlas/disease/hypercholesterolemia-familial-1/), [familial hypercholesterolemia](https://sugi.bio/atlas/disease/familial-hypercholesterolemia/).

**Reported phenotype names (ClinVar):** Hypercholesterolemia, familial, 1, not provided, Familial hypercholesterolemia, Cardiovascular phenotype, Dyslipidemia, Familial hypercholesterolemias, Familial hypercholesterolaemia, none provided, LDL RECEPTOR DISORDER, Hyperlipoproteinemia Type IIa.

## Same-residue context {#hotspot}

Residue **181** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [LDLR p.Pro181Ter](/variant/ldlr-p-pro181ter), [LDLR p.Pro181Leu](/variant/ldlr-p-pro181leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related LDLR variant pages (same residue, condition, or type): [LDLR p.Pro181Leu](/variant/ldlr-p-pro181leu), [LDLR p.Pro181=](/variant/ldlr-p-pro181), [LDLR p.Pro181Ter](/variant/ldlr-p-pro181ter), [LDLR c.1186+5G>A](/variant/ldlr-c-1186-plus-5g-a), [LDLR c.1359-1G>A](/variant/ldlr-c-1359-minus-1g-a), [LDLR c.1359-5C>G](/variant/ldlr-c-1359-minus-5c-g), [LDLR c.1705+2T>C](/variant/ldlr-c-1705-plus-2t-c), [LDLR c.190+4A>T](/variant/ldlr-c-190-plus-4a-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 183089). 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.*