# NM_000527.5(LDLR):c.1784G>A (p.Arg595Gln)

https://sugi.bio/variant/ldlr-p-arg595gln

## Summary

**LDLR p.Arg595Gln (c.1784G>A)** is classified **Pathogenic** in LDLR (ClinVar, Expert panel, 27 submitters; last evaluated 2022-02-02). AlphaMissense: likely benign (0.1949); Very rare (popmax 0.00446%, eas); Associated with hypercholesterolemia, familial, 1.

**At a glance:** Pathogenic · review: Expert panel · rsID rs201102492 · 27 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00446%, eas)

## For patients & families {#patients}

This is a change in the LDLR gene that is reported as disease-causing, though the computational evidence is not fully concordant, submitted by 27 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.Arg595Gln |
| Coding change (HGVS c.) | c.1784G>A |
| MANE Select transcript | [NM_000527](https://www.ncbi.nlm.nih.gov/nuccore/NM_000527) |
| dbSNP | [rs201102492](https://www.ncbi.nlm.nih.gov/snp/rs201102492/) |
| Variant type | single nucleotide variant |
| Location | chr19:11116937-11116937 (GRCh38) |
| ClinVar | [VCV183126](https://www.ncbi.nlm.nih.gov/clinvar/variation/183126/) |

**All HGVS expressions:** `LRG_274:g.32557G>A`, `LRG_274t1:c.1784G>A`, `NC_000019.10:g.11116937G>A`, `NC_000019.9:g.11227613G>A`, `NG_009060.1:g.32557G>A`, `NM_000527.5:c.1784G>A`, `NM_001195798.2:c.1784G>A`, `NM_001195799.2:c.1661G>A`, `NM_001195800.2:c.1280G>A`, `NM_001195803.2:c.1403G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.1949) — ⚠ discordant with the pathogenic call
- REVEL 0.956 (strongly pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -10.788 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 11.52, GERP 2.48, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 32.0**. 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 **0.00446%** (eas) · FAF95 0.000739% · FAF99 0.000276% · 2/44,872 in the highest group · 26/1,614,046 alleles overall — very rare (popmax 0.00446%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.025% | 4,002 |
| East Asian (grpmax) | 0.00446% | 22,436 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,504 |
| South Asian | 0.0011% | 91,086 |
| European (non-Finnish) | 0.000508% | 196,665 |

Finnish 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 2022-02-02.

**Submitter consensus:** conflicting (17 Pathogenic, 7 Likely pathogenic, 2 Uncertain significance, 1 not provided).

**Submission history:** 22 submissions (2016–2026); 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`, `PS3_Supporting`, `PS4`, `PP3`, `PP4`, `PM3`, `PM5`.
*Considered but not met:* `PM6`, `PVS1`, `PS1`, `PS2`, `PM1`, `PP1`, `BS2`, `BS1`, `BS4`, `BS3`, `BP7`, `BP4`, `BP2`, `BA1`, `PM4`.
Inheritance: Semidominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000527.5(LDLR):c.1784G>A (p.Arg595Gln) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PM5, PS3_supporting, PS4, PP4, PM3) 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 - PopMax MAF = 0.0002389 (0.02389%) in European (Finnish) exomes+genomes (gnomAD v2.1.1), since this is a founder effect variant in Finnish population (PMID: 11585102) we can consider PopMax MAF = 0.00005012 (0.005012%) in East Asian exomes+genomes (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.956. It is above 0.75, so PP3 is Met. PM5 - 2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp) (ClinVar ID: 161290)     - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1784G>T (p.Arg595Leu) (ClinVar ID: 252029)     - Likely pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met. PS3_supporting - Level 3 assay:  PMID 11585102: Heterozygous patient cells, 125I-LDL assays - result - 70% LDL-LDLR binding, 54-49% LDL-LDLR uptake and degradation. ---- functional study is consistent with damaging effect, so PS3_Supporting is Met. PS4 - Variant meets PM2 and is identified in 11 unrelated index cases: 1 index case with Simon Broome definite criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), 4 index cases with DLCN criteria for FH (LDL > 95th percentile and presence of tendon xanthomas) from Finland (PMID: 11585102), 1 index case with FH criteria suggested by the Japan Atherosclerosis Society (TC > 260 mg/dL with tendon xanthomas OR TC > 260 mg/dL and TC > 260 mg/dL with tendon xanthomas in first or second degree relatives) from Japan ( PMID: 18718593), 1 index case with DLCN criteria for FH (score=8) from Sweden (PMID: 29974534), 1 index case with DLCN criteria for FH (score>=6) from Argentina (PMID: 30270055), 2 index cases with DLCN criteria for FH (score>=6) from Russia (PMID: 33418990), 1 index case with homozygous FH phenotype (LDL = 16 mmol/L) from The Netherlands (PMID: 24585268), so PS4 is Met. PP4 - Variant meets PM2 and is identified in 11 unrelated index cases as described before, so PP4 is Met. PM3 - Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL = 16 mmol/L) and LDLR variant c.(1705+1_1706-1)_(*2514_?)del (described as 16kb deletion exon 12-18) (PMID: 24585268), classified as Pathogenic by these guidelines, in trans, so PM3 is Met.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50004 · approved 2022-02-02 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/812ea6ba-58f9-4dc4-b88d-13dc9626d34f).*
*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 | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-12 |
| Genetic Services Laboratory, University of Chicago | Likely pathogenic | criteria provided, single submitter | clinical testing | 2018-08-13 |
| All of Us Research Program, National Institutes of Health | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-15 |
| Dept. of Genetics and Pharmacogenomics, Merck Research Labs | not provided | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-27 |
| Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub | Pathogenic | criteria provided, single submitter | clinical testing | 2026-04-09 |
| Robarts Research Institute, Western University | Likely pathogenic | criteria provided, single submitter | clinical testing |  |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | Pathogenic | no assertion criteria provided | research |  |
| Iberoamerican FH Network | Uncertain significance | criteria provided, single submitter | research | 2016-03-01 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-11-30 |
| Clinical Genetics Laboratory, Region Ostergotland | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-03-24 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-01 |
| Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation | Likely pathogenic | criteria provided, single submitter | clinical testing | 2016-11-05 |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-30 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-05-05 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2022-11-09 |
| Juno Genomics, Hangzhou Juno Genomics, Inc | Pathogenic | criteria provided, single submitter | clinical testing |  |
| Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-27 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-05 |
| LDLR-LOVD, British Heart Foundation | Likely pathogenic | criteria provided, single submitter | literature only | 2016-03-25 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-05-05 |
| ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Pathogenic | reviewed by expert panel | curation | 2022-02-02 |
| Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine | Uncertain significance | criteria provided, single submitter | research |  |
| Color Diagnostics, LLC DBA Color Health | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-17 |
| Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-24 |
| Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Pathogenic | no assertion criteria provided | clinical testing | 2023-12-05 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-01 |

## 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, Cardiovascular phenotype, Dyslipidemia, LDLR-related familial hypercholesterolemia, LDLR-related disorder, LDLR-related condition, Familial hypercholesterolemias, Familial hypercholesterolaemia.

## Same-residue context {#hotspot}

Residue **595** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [LDLR p.Arg595Trp](/variant/ldlr-p-arg595trp), [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.Arg595Leu](/variant/ldlr-p-arg595leu), [LDLR p.Arg595Trp](/variant/ldlr-p-arg595trp), [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 2026-10-14); 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 183126). 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.*