# NM_000527.5(LDLR):c.1959T>C (p.Val653=)

https://sugi.bio/variant/ldlr-p-val653

## Summary

**LDLR p.Val653= (c.1959T>C)** is classified **Benign/Likely benign** in LDLR (ClinVar, Multiple submitters, 22 submitters; last evaluated 2026-02-04). Common (popmax 52.1%, amr) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs5925 · 22 submitters · 3 linked conditions · common (popmax 52.1%, amr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the LDLR gene that is classified as benign/likely benign — not considered disease-causing, submitted by 22 submitters, and is linked to Cardiovascular phenotype.

*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:** [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.Val653= |
| Coding change (HGVS c.) | c.1959T>C |
| MANE Select transcript | [NM_000527](https://www.ncbi.nlm.nih.gov/nuccore/NM_000527) |
| dbSNP | [rs5925](https://www.ncbi.nlm.nih.gov/snp/rs5925/) |
| Variant type | single nucleotide variant |
| Location | chr19:11120205-11120205 (GRCh38) |
| ClinVar | [VCV252131](https://www.ncbi.nlm.nih.gov/clinvar/variation/252131/) |

**All HGVS expressions:** `LRG_274:g.35825T>C`, `LRG_274t1:c.1959T>C`, `NC_000019.10:g.11120205T>C`, `NC_000019.9:g.11230881T>C`, `NG_009060.1:g.35825T>C`, `NM_000527.5:c.1959T>C`, `NM_001195798.2:c.1959T>C`, `NM_001195799.2:c.1836T>C`, `NM_001195800.2:c.1455T>C`, `NM_001195803.2:c.1578T>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 52.1%, amr) — too common for a highly-penetrant pathogenic allele.

- **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 0.069, GERP -1.03, phastCons 0.904 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 5.78**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for LDLR (717 scored positions, the nearest 7 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **52.1%** (amr) · FAF95 51.7% · FAF99 51.5% · 31,260/59,956 in the highest group · 695,024/1,613,320 alleles overall — common (popmax 52.1%, amr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 52.1% | 2 |
| Finnish (not grpmax-eligible) | 47.9% | 2 |
| Middle Eastern | 45.5% | 2 |
| European (non-Finnish) | 44.7% | 2 |
| Ashkenazi Jewish (not grpmax-eligible) | 43.4% | 2 |
| South Asian | 43.4% | 2 |
| Remaining individuals (not grpmax-eligible) | 42.2% | 2 |
| Amish (not grpmax-eligible) | 34.7% | 3 |
| African / African-American | 19.7% | 5 |
| East Asian | 19.6% | 5 |

*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 **653** 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (20 Benign, 2 Likely benign).

**Submission history:** 17 submissions (2014–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2018-02-07 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-03-06 |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Benign | no assertion criteria provided | clinical testing |  |
| Color Diagnostics, LLC DBA Color Health | Benign | criteria provided, single submitter | clinical testing | 2017-06-22 |
| Cohesion Phenomics | Benign | no assertion criteria provided | clinical testing | 2023-02-09 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2015-12-08 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Benign | criteria provided, single submitter | clinical testing | 2025-04-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| LDLR-LOVD, British Heart Foundation | Benign | criteria provided, single submitter | literature only | 2016-03-25 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Benign | criteria provided, single submitter | research | 2016-03-01 |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | Benign | no assertion criteria provided | research |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2016-09-30 |
| Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen | Likely benign | criteria provided, single submitter | clinical testing | 2018-07-16 |
| Natera, Inc. | Benign | no assertion criteria provided | clinical testing | 2020-09-16 |
| GENinCode PLC | Benign | criteria provided, single submitter | clinical testing | 2022-07-14 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-06-10 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2014-02-26 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-07-25 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-28 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, Hypercholesterolemia, familial, 1, not specified, Familial hypercholesterolemia, not provided, Familial hypercholesterolemias, Familial hypercholesterolaemia, AllHighlyPenetrant, none provided, HYPERCHOLESTEROLEMIA, FAMILIAL, MODIFIER OF.

## Pharmacogenomics (PharmGKB) {#pgx}

Clinical drug-response annotations:

| Drug(s) | Evidence level | Category | Phenotype |
| --- | --- | --- | --- |
| lovastatin | 3 | Efficacy |  |
*PharmGKB levels 1A/1B (highest) → 4. Discuss any medication decision with your prescriber — reference information, not advice.*

## Similar variants {#similar}

Related LDLR variant pages (same residue, condition, or type): [LDLR p.Val653Gly](/variant/ldlr-p-val653gly), [LDLR p.Val653Ile](/variant/ldlr-p-val653ile), [LDLR p.Val653Phe](/variant/ldlr-p-val653phe), [LDLR p.Val653Ala](/variant/ldlr-p-val653ala), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 252131). 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.*