# NM_000527.5(LDLR):c.1049G>C (p.Arg350Pro)

https://sugi.bio/variant/ldlr-p-arg350pro

## Summary

**LDLR p.Arg350Pro (c.1049G>C)** is classified **Likely pathogenic** in LDLR (ClinVar, Expert panel, 17 submitters; last evaluated 2023-04-28). AlphaMissense: likely pathogenic (0.5746); Very rare (popmax 0.00167%, amr); Associated with hypercholesterolemia, familial, 1.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs875989914 · 17 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the LDLR gene that is considered likely disease-causing, submitted by 17 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.Arg350Pro |
| Coding change (HGVS c.) | c.1049G>C |
| MANE Select transcript | [NM_000527](https://www.ncbi.nlm.nih.gov/nuccore/NM_000527) |
| dbSNP | [rs875989914](https://www.ncbi.nlm.nih.gov/snp/rs875989914/) |
| Variant type | single nucleotide variant |
| Location | chr19:11110760-11110760 (GRCh38) |
| ClinVar | [VCV226343](https://www.ncbi.nlm.nih.gov/clinvar/variation/226343/) |

**All HGVS expressions:** `LRG_274:g.26380G>C`, `LRG_274t1:c.1049G>C`, `NC_000019.10:g.11110760G>C`, `NC_000019.9:g.11221436G>C`, `NG_009060.1:g.26380G>C`, `NM_000527.5:c.1049G>C`, `NM_001195798.2:c.1049G>C`, `NM_001195799.2:c.926G>C`, `NM_001195800.2:c.545G>C`, `NM_001195803.2:c.668G>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.5746) — concordant with the pathogenic call
- REVEL 0.648 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.832 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP -0.622, GERP -4.87 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 21.0**. 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 **0.00167%** (amr) · FAF95 0.000247% · FAF99 0.000159% · 1/59,988 in the highest group · 8/1,613,242 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 59,988 |
| European (non-Finnish) | 0.000593% | 168,554 |

*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, triplosensitivity 0 (0–3 scale). *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 **350** lies in the egf-like 1 domain; a UniProt-annotated variant site (in fhcl1; likely pathogenic); a turn.

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.Arg350Pro falls in the egf-like 1 domain.


### 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 2023-04-28.

**Submitter consensus:** conflicting (11 Likely pathogenic, 5 Pathogenic, 1 Likely Pathogenic).

**Submission history:** 17 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`, `PS4_Supporting`, `PS3_Moderate`, `PP1_Moderate`, `PP4`.
*Considered but not met:* `PVS1`, `PM1`, `PP3`, `BS1`, `BS4`, `BS3`, `BP4`, `BA1`.
Inheritance: Semidominant inheritance.

> **Curation rationale (ClinGen, verbatim):** NM_000527.4(LDLR): c.1049G>C (p.Arg350Pro) variant is classified as Likely Pathogenic  for Familial Hypercholesterolemia by applying evidence codes PM2, PS4_Supporting, PP1_Moderate, PP4, and PS3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:    . PM2: This variant is absent from gnomAD (gnomAD v2.1.1).  . PS4_Supporting: Variant meets PM2 and is identified in 5 index cases: 4 cases with DLCN criteria>=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), 1 case with DLCN criteria>=6 in Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France  . PP1_Moderate: Variant segregates with FH phenotype in 5 informative meioses in 3 families from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA). 3 relatives without the phenotype and the variant, 2 relatives with the phenotype and the variant  . PP4: Variant meets PM2 and is identified in at least 1 index case with DLCN>=6 after alternative causes of high cholesterol were excluded. Data is from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) and Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France.  . PS3_moderate: Level 2 assays: PMID 15100232 Heterologous cells (CHO)  ACS, WB and NMR Spectroscopy <10% cell surface LDLR, 65% binding, (WB), ~10% expression
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50004 · approved 2023-04-28 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/baa65fd0-7621-400f-b358-8c8d1aaafcc5).*
*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 | 2023-02-13 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-19 |
| Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Pathogenic | criteria provided, single submitter | clinical testing | 2026-05-26 |
| Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Pathogenic | criteria provided, single submitter | clinical testing | 2023-09-11 |
| LDLR-LOVD, British Heart Foundation | Likely pathogenic | criteria provided, single submitter | literature only | 2016-03-25 |
| ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Likely pathogenic | reviewed by expert panel | curation | 2023-04-28 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-06-16 |
| All of Us Research Program, National Institutes of Health | Likely Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-29 |
| Color Diagnostics, LLC DBA Color Health | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-05-26 |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-11-14 |
| Clinical Genomic Analysis (GENYSIS) Core, University of North Carolina at Chapel Hill | Likely pathogenic | criteria provided, single submitter | research | 2025-09-25 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-09-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-13 |
| LIPIGEN - Lipid Transport Disorders Italian Genetic Network | Likely pathogenic | criteria provided, single submitter | research | 2026-02-11 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-07-08 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-04-06 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-08-08 |

## 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, Familial hypercholesterolemia, not provided, Cardiovascular phenotype, LDLR-related disorder, LDLR-Related Familial Hypercholesterolemia, Autosomal Dominant, HYPERCHOLESTEROLEMIA, FAMILIAL, MODIFIER OF, LDL RECEPTOR DISORDER, Hyperlipoproteinemia Type IIa, HYPER-LOW-DENSITY-LIPOPROTEINEMIA.

## Same-residue context {#hotspot}

Residue **350** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [LDLR p.Arg350Ter](/variant/ldlr-p-arg350ter), [LDLR p.Arg350fs](/variant/ldlr-p-arg350fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related LDLR variant pages (same residue, condition, or type): [LDLR p.Arg350Ter](/variant/ldlr-p-arg350ter), [LDLR p.Arg350Gln](/variant/ldlr-p-arg350gln), [LDLR p.Arg350=](/variant/ldlr-p-arg350), [LDLR p.Arg350Gly](/variant/ldlr-p-arg350gly), [LDLR p.Arg350fs](/variant/ldlr-p-arg350fs), [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).

### 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 226343). 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.*