# NM_000527.5(LDLR):c.1216C>A (p.Arg406=)

https://sugi.bio/variant/ldlr-p-arg406

## Summary

**LDLR p.Arg406= (c.1216C>A)** is classified **Likely pathogenic** in LDLR (ClinVar, Expert panel, 18 submitters; last evaluated 2021-06-08). Very rare (popmax 0.00223%, eas); Associated with hypercholesterolemia, familial, 1.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs121908043 · 18 submitters · 2 linked conditions · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the LDLR gene that is considered likely disease-causing, submitted by 18 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.Arg406= |
| Coding change (HGVS c.) | c.1216C>A |
| MANE Select transcript | [NM_000527](https://www.ncbi.nlm.nih.gov/nuccore/NM_000527) |
| dbSNP | [rs121908043](https://www.ncbi.nlm.nih.gov/snp/rs121908043/) |
| Variant type | single nucleotide variant |
| Location | chr19:11113307-11113307 (GRCh38) |
| ClinVar | [VCV3746](https://www.ncbi.nlm.nih.gov/clinvar/variation/3746/) |

**All HGVS expressions:** `LRG_274:g.28927C>A`, `LRG_274t1:c.1216C>A`, `NC_000019.10:g.11113307C>A`, `NC_000019.9:g.11223983C>A`, `NG_009060.1:g.28927C>A`, `NM_000527.5:c.1216C>A`, `NM_001195798.2:c.1216C>A`, `NM_001195799.2:c.1093C>A`, `NM_001195800.2:c.712C>A`, `NM_001195803.2:c.835C>A`

## Computational & population evidence {#evidence}

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

- **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 **acceptor gain** (Δ 1.00) — consistent with the pathogenic call
- Conservation: phyloP 7.544, GERP 1.46, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 22.7**. 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 **0.43**, donor loss **0.00**, acceptor gain **1.00**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.43**, donor loss **0.00**, acceptor gain **1.00**, donor gain **0.00**.
- Pangolin: Δ**0.84** (gain), gain 0.84 / loss 0.61. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · 1/44,870 in the highest group · 1/1,613,508 alleles overall — very rare (popmax 0.00223%, eas).

*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 **406** lies in a UniProt-annotated variant site (in fhcl1; likely pathogenic); a UniProt-annotated variant site (in fhcl1; pathogenic); a β-strand.

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.


### 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 2021-06-08.

**Submitter consensus:** conflicting (13 Pathogenic, 5 Likely pathogenic).

**Submission history:** 15 submissions (2008–2025); 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`, `PP4`, `PM3`.
*Considered but not met:* `PM6`, `PVS1`, `PS1`, `PS2`, `PM1`, `PP1`, `PP2`, `PP3`, `BS2`, `BS1`, `BS4`, `BS3`, `BP5`, `BP7`, `PM5`, `BP4`, `BP3`, `BP1`, `BP2`, `BA1`, `PM4`.
Inheritance: Semidominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000527.5(LDLR):c.1216C>A (p.Arg406=) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM3, PS3_Moderate,  PP4 and PS4_Supportive) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755).  The supporting evidence is as follows:   PM2 - PopMax MAF = 0.00005441 (0.005%) in East Asian exomes (gnomAD v2.1.1). PM3 - Variant meets PM2 and is identified in one compound heterozygote with a homozygous FH phenotype published in PMID 28028493 (Patient F3 compound with NM_000527.5(LDLR):c.760C>T (p.Gln254Ter) (ClinVar ID 251436), LDLc: 18.21 mmol/l). Additional variant classified as Pathogenic by these guidelines. PS3_moderate - Level 2 FS: PMID: 19371225 - Htz patient's Epstein-Barr virus transformed lymphocytes. RNA assays. Mutant mRNA 25%-45% of total amount. PP4 - Variant meets PM2. Variant identified in 2 index cases. PS4_supporting - Variant meets PM2. Variant identified in 2 index cases.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50004 · approved 2021-06-08 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/1bb8fe4b-fd4a-4ab2-952f-71ea0f6664c5).*
*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 |
| --- | --- | --- | --- | --- |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2019-12-30 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-24 |
| Color Diagnostics, LLC DBA Color Health | Pathogenic | criteria provided, single submitter | clinical testing | 2023-05-08 |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-12-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-29 |
| Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Pathogenic | criteria provided, single submitter | curation | 2016-03-01 |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | Pathogenic | no assertion criteria provided | research |  |
| ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Likely pathogenic | reviewed by expert panel | curation | 2021-06-08 |
| Medical Laboratory Center, Huzhou Maternal and Child Health Hospital | Pathogenic | no assertion criteria provided | research |  |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-04 |
| Juno Genomics, Hangzhou Juno Genomics, Inc | Likely pathogenic | criteria provided, single submitter | clinical testing |  |
| Division of Genetic & Genomic Pathology, Hong Kong Children's Hospital | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-09-20 |
| LDLR-LOVD, British Heart Foundation | Pathogenic | criteria provided, single submitter | literature only | 2016-03-25 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2008-06-01 |
| Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | Likely pathogenic | criteria provided, single submitter | research | 2019-03-03 |
| Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II | Pathogenic | criteria provided, single submitter | clinical testing | 2021-05-24 |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-11 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-06 |

## 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, Cardiovascular phenotype, not provided, Familial hypercholesterolemias, Familial hypercholesterolaemia, none provided, HYPERCHOLESTEROLEMIA, FAMILIAL, MODIFIER OF, LDL RECEPTOR DISORDER, Hyperlipoproteinemia Type IIa.

## Same-residue context {#hotspot}

Residue **406** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [LDLR p.Arg406Trp](/variant/ldlr-p-arg406trp), [LDLR p.Arg406Pro](/variant/ldlr-p-arg406pro), [LDLR p.Arg406Gln](/variant/ldlr-p-arg406gln). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related LDLR variant pages (same residue, condition, or type): [LDLR p.Arg406Gln](/variant/ldlr-p-arg406gln), [LDLR p.Arg406Pro](/variant/ldlr-p-arg406pro), [LDLR p.Arg406Trp](/variant/ldlr-p-arg406trp), [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 3746). 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.*