# NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp)

https://sugi.bio/variant/ldlr-p-arg595trp

## Summary

**LDLR p.Arg595Trp (c.1783C>T)** is classified **Pathogenic** in LDLR (ClinVar, Expert panel, 32 submitters; last evaluated 2021-06-09). AlphaMissense: ambiguous (0.3756); Very rare (popmax 0.00446%, eas); Associated with hypercholesterolemia, familial, 1.

**At a glance:** Pathogenic · review: Expert panel · rsID rs373371572 · 32 submitters · 2 linked conditions · AlphaMissense ambiguous · very rare (popmax 0.00446%, eas)

## For patients & families {#patients}

This is a change in the LDLR gene that is considered disease-causing, submitted by 32 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.Arg595Trp |
| Coding change (HGVS c.) | c.1783C>T |
| MANE Select transcript | [NM_000527](https://www.ncbi.nlm.nih.gov/nuccore/NM_000527) |
| dbSNP | [rs373371572](https://www.ncbi.nlm.nih.gov/snp/rs373371572/) |
| Variant type | single nucleotide variant |
| Location | chr19:11116936-11116936 (GRCh38) |
| ClinVar | [VCV161290](https://www.ncbi.nlm.nih.gov/clinvar/variation/161290/) |

**All HGVS expressions:** `LRG_274:g.32556C>T`, `LRG_274t1:c.1783C>T`, `NC_000019.10:g.11116936C>T`, `NC_000019.9:g.11227612C>T`, `NG_009060.1:g.32556C>T`, `NM_000527.5:c.1783C>T`, `NM_001195798.2:c.1783C>T`, `NM_001195799.2:c.1660C>T`, `NM_001195800.2:c.1279C>T`, `NM_001195803.2:c.1402C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.3756) — no call either way
- REVEL 0.89 (moderately pathogenic-leaning)
- SaProt LLR -12.748 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense is indeterminate
- Conservation: phyloP 1.449, GERP 0.262, phastCons 0.971 — weakly conserved position
- CADD: **PHRED 25.9**. 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: **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 2 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 **0.00446%** (eas) · FAF95 0.000875% · FAF99 0.000605% · 2/44,884 in the highest group · 26/1,613,914 alleles overall — very rare (popmax 0.00446%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,827 |
| East Asian (grpmax) | 0.00446% | 22,442 |
| South Asian | 0.00329% | 30,361 |
| African / African-American | 0.00267% | 37,447 |
| Admixed American | 0.00167% | 59,962 |
| European (non-Finnish) | 0.00127% | 78,666 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **595** lies in a UniProt-annotated variant site (in fhcl1; pathogenic).

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}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2021-06-09.

**Submitter consensus:** conflicting (22 Pathogenic, 5 Likely pathogenic, 5 Uncertain significance).

**Submission history:** 30 submissions (2014–2025); classifications have differed over time.

**ClinGen expert panel:** Pathogenic — Familial Hypercholesterolemia VCEP (hypercholesterolemia, familial). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2`, `PP1_Strong`, `PS4`, `PP3`, `PP4`.
*Considered but not met:* `PM6`, `PVS1`, `PS1`, `PS2`, `PS3`, `PM1`, `PP2`, `BS2`, `PM3`, `BS1`, `BS4`, `BS3`, `BP5`, `BP7`, `PM5`, `BP4`, `BP3`, `BP1`, `BP2`, `BA1`, `PM4`.
Inheritance: Semidominant inheritance.

> **Curation rationale (ClinGen, verbatim):** NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM2, PP3 and PP4) 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:   PS4 - Variant meets PM2. Variant identified in 12 index cases. PP1_strong - 10 informative meioses identified by Laboratory of Genetics and Molecular Cardiology. PM2 - PopMax MAF = 0.00001548 (0.0015%) in European non-Finnish (gnomAD v2.1.1).  PP3 - REVEL: 0,89.  PP4 - Variant meets PM2. Variant identified in 12 index cases fulfilling validated clinical criteria for FH (6 cases with Simon-Broome or DLCN criteria from Ambry Genetics; 2 cases with Simon-Broome from Color laboratory; 3 cases with Simon-Broome criteria from Laboratory of Genetics and Molecular Cardiology; 1 case with Simon-Broome criteria from GeneDx).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50004 · approved 2021-06-09 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/ba5d5793-ffd3-48df-89c0-24c7600a8a6d).*
*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 |
| --- | --- | --- | --- | --- |
| Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix | Likely pathogenic | criteria provided, single submitter | clinical testing | 2016-12-16 |
| Laboratory of Genetics and Molecular Cardiology, University of São Paulo | Uncertain significance | criteria provided, single submitter | research | 2016-03-01 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-19 |
| U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Pathogenic | criteria provided, single submitter | clinical testing | 2017-03-30 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-30 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-02-15 |
| LDLR-LOVD, British Heart Foundation | Likely pathogenic | criteria provided, single submitter | literature only | 2016-03-25 |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | Pathogenic | no assertion criteria provided | research |  |
| Fundacion Hipercolesterolemia Familiar | Uncertain significance | criteria provided, single submitter | research | 2016-03-01 |
| Athena Diagnostics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2017-06-16 |
| Iberoamerican FH Network | Uncertain significance | criteria provided, single submitter | research | 2016-03-01 |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-03-16 |
| Institute of Human Genetics, University of Leipzig Medical Center | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-09-07 |
| ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Pathogenic | reviewed by expert panel | curation | 2021-06-09 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-10-07 |
| Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Pathogenic | no assertion criteria provided | clinical testing | 2023-10-09 |
| Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2021-05-12 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2023-07-17 |
| All of Us Research Program, National Institutes of Health | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-06 |
| Institute of Human Genetics Munich, TUM University Hospital | Likely pathogenic | criteria provided, single submitter | clinical testing | 2018-12-27 |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2022-02-14 |
| Color Diagnostics, LLC DBA Color Health | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-24 |
| GENinCode PLC | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-07 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2022-07-27 |
| Juno Genomics, Hangzhou Juno Genomics, Inc | Pathogenic | criteria provided, single submitter | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-21 |
| CSER _CC_NCGL, University of Washington | Uncertain significance | no assertion criteria provided | research | 2014-06-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2019-09-30 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2022-10-07 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Pathogenic | criteria provided, single submitter | research | 2024-03-17 |
| Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-17 |
| Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Pathogenic | no assertion criteria provided | clinical testing | 2023-09-11 |

## 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, Hypercholesterolemia, Cardiovascular phenotype, LDLR-related disorder, LDLR-related condition, Familial hypercholesterolaemia, Familial hypercholesterolemias, none provided.

## Same-residue context {#hotspot}

Residue **595** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [LDLR p.Arg595Gln](/variant/ldlr-p-arg595gln), [LDLR p.Arg595fs](/variant/ldlr-p-arg595fs), [LDLR p.Arg595Leu](/variant/ldlr-p-arg595leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related LDLR variant pages (same residue, condition, or type): [LDLR p.Arg595Gln](/variant/ldlr-p-arg595gln), [LDLR p.Arg595Leu](/variant/ldlr-p-arg595leu), [LDLR p.Arg595=](/variant/ldlr-p-arg595), [LDLR p.Arg595fs](/variant/ldlr-p-arg595fs), [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 161290). 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.*