# NM_000527.5(LDLR):c.1279A>C (p.Arg427=)

https://sugi.bio/variant/ldlr-p-arg427

## Summary

**LDLR p.Arg427= (c.1279A>C)** is classified **Likely benign** in LDLR (ClinVar, Expert panel, 10 submitters; last evaluated 2023-01-27). Very rare (popmax 0.00814%, nfe); Associated with hypercholesterolemia, familial, 1.

**At a glance:** Likely benign · review: Expert panel · rsID rs371355878 · 10 submitters · 2 linked conditions · very rare (popmax 0.00814%, nfe)

## For patients & families {#patients}

This is a change in the LDLR gene that is classified as likely benign — not considered disease-causing, submitted by 10 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.Arg427= |
| Coding change (HGVS c.) | c.1279A>C |
| MANE Select transcript | [NM_000527](https://www.ncbi.nlm.nih.gov/nuccore/NM_000527) |
| dbSNP | [rs371355878](https://www.ncbi.nlm.nih.gov/snp/rs371355878/) |
| Variant type | single nucleotide variant |
| Location | chr19:11113370-11113370 (GRCh38) |
| ClinVar | [VCV251764](https://www.ncbi.nlm.nih.gov/clinvar/variation/251764/) |

**All HGVS expressions:** `LRG_274:g.28990A>C`, `LRG_274t1:c.1279A>C`, `NC_000019.10:g.11113370A>C`, `NC_000019.9:g.11224046A>C`, `NG_009060.1:g.28990A>C`, `NM_000527.5:c.1279A>C`, `NM_001195798.2:c.1279A>C`, `NM_001195799.2:c.1156A>C`, `NM_001195800.2:c.775A>C`, `NM_001195803.2:c.898A>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 9.104, GERP 1.54, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 12.33**. 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 **0.00814%** (nfe) · FAF95 0.00681% · FAF99 0.00633% · 96/1,180,030 in the highest group · 96/1,613,792 alleles overall — very rare (popmax 0.00814%, nfe).

*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 **427** lies in 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 benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2023-01-27.

**Submitter consensus:** conflicting (7 Likely benign, 2 Likely Benign, 1 Uncertain significance).

**Submission history:** 10 submissions (2016–2025); classifications have differed over time.

**ClinGen expert panel:** Likely Benign — Familial Hypercholesterolemia VCEP (hypercholesterolemia, familial). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2`, `PP4`, `BP7`, `BP4`, `BP2`.
*Considered but not met:* `PM6`, `PVS1`, `PS1`, `PS2`, `PS3`, `PS4`, `PM1`, `PP1`, `PP2`, `PP3`, `BS2`, `PM3`, `BS1`, `BS4`, `BS3`, `PM5`, `BP3`, `BP1`, `BA1`, `PM4`.
Inheritance: Semidominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000527.5(LDLR):c.1279A>C (p.Arg427=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BP2, BP4, BP7, PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023.  The supporting evidence is as follows: PM2: PopMax MAF = 0.00006976 (0.006976%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1). BP4: No REVEL, splicing evaluation required. Functional data on splicing not available. A) variant not on limits B) does not create AG/GT C) variant is exonic and there is no AG/GT nearby     Variant is not predicted to alter splicing. --- BP4 is met. BP7: Variant is synonymous and meets BP4. BP2: Variant identified in an index case with heterozygous FH phenotype (LDL-C=170mg/dL on statins) and LDLR c.530C>T (p.Ser177Leu) (confirmed in trans), classified as Pathogenic by these guidelines, from Cardiovascular Research Group, Instituto Nacional de Saúde Dr. Ricardo Jorge, Portugal. PP4: Variant meets PM2 and is identified in 1 index case with possible FH by Simon Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saúde Dr. Ricardo Jorge, Portugal. Variant has 3 Supporting evidence codes towards Benign, enough to classify as Likely Benign and only 1 Moderate plus 1 Supporting evidence codes towards Pathogenic, so we are confident in classifying this variant as Likely Benign.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50004 · approved 2023-01-27 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/e1a0ec5e-a3f6-416d-b5d0-f502d242d549).*
*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 |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Likely benign | no assertion criteria provided | clinical testing | 2020-09-16 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-04-19 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-07-19 |
| LDLR-LOVD, British Heart Foundation | Likely benign | criteria provided, single submitter | literature only | 2016-03-25 |
| Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Uncertain significance | criteria provided, single submitter | research | 2016-03-01 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2017-07-17 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2024-02-05 |
| GENinCode PLC | Likely benign | criteria provided, single submitter | clinical testing | 2023-03-10 |
| ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Likely Benign | reviewed by expert panel | curation | 2023-01-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-28 |

## 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 specified, AllHighlyPenetrant, Familial hypercholesterolaemia, Familial hypercholesterolemias, LDLR-Related Familial Hypercholesterolemia, Autosomal Dominant, HYPERCHOLESTEROLEMIA, FAMILIAL, MODIFIER OF, LDL RECEPTOR DISORDER.

## Similar variants {#similar}

Related LDLR variant pages (same residue, condition, or type): [LDLR p.Arg427Lys](/variant/ldlr-p-arg427lys), [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), [LDLR c.2140+1G>A](/variant/ldlr-c-2140-plus-1g-a), [LDLR c.2389+2T>G](/variant/ldlr-c-2389-plus-2t-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 251764). 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.*