# NM_000527.5(LDLR):c.2113G>C (p.Ala705Pro)

https://sugi.bio/variant/ldlr-p-ala705pro

## Summary

**LDLR p.Ala705Pro (c.2113G>C)** is classified **Uncertain significance** in LDLR (ClinVar, Expert panel, 15 submitters; last evaluated 2022-02-11). AlphaMissense: likely pathogenic (0.7084); Very rare (popmax 8.47e-05%, nfe); Associated with hypercholesterolemia, familial, 1.

**At a glance:** Uncertain significance · review: Expert panel · rsID rs193922570 · 15 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the LDLR gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 15 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.Ala705Pro |
| Coding change (HGVS c.) | c.2113G>C |
| MANE Select transcript | [NM_000527](https://www.ncbi.nlm.nih.gov/nuccore/NM_000527) |
| dbSNP | [rs193922570](https://www.ncbi.nlm.nih.gov/snp/rs193922570/) |
| Variant type | single nucleotide variant |
| Location | chr19:11120495-11120495 (GRCh38) |
| ClinVar | [VCV36459](https://www.ncbi.nlm.nih.gov/clinvar/variation/36459/) |

**All HGVS expressions:** `LRG_274:g.36115G>C`, `LRG_274t1:c.2113G>C`, `NC_000019.10:g.11120495G>C`, `NC_000019.9:g.11231171G>C`, `NG_009060.1:g.36115G>C`, `NM_000527.5:c.2113G>C`, `NM_001195798.2:c.2113G>C`, `NM_001195799.2:c.1990G>C`, `NM_001195800.2:c.1609G>C`, `NM_001195803.2:c.1606+262G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.7084)
- REVEL 0.78 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.402 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 8.385, GERP 1.17, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 23.7**. 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.*
- 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 **8.47e-05%** (nfe) · 1/1,180,030 in the highest group · 1/1,613,482 alleles overall — very rare (popmax 8.47e-05%, 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 **705** lies in the egf-like 3 domain.

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. p.Ala705Pro falls in the egf-like 3 domain.


### 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}

**Uncertain significance** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2022-02-11.

**Submitter consensus:** conflicting (7 Pathogenic, 4 Likely pathogenic, 2 Uncertain significance, 1 pathogenic, 1 Uncertain Significance).

**Submission history:** 12 submissions (2016–2025); classifications have differed over time.

**ClinGen expert panel:** Uncertain Significance — Familial Hypercholesterolemia VCEP (hypercholesterolemia, familial). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2`, `PP3`, `PP4`.
*Considered but not met:* `PS3`, `PM5`.
Inheritance: Semidominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000527.5 (LDLR): c.2113G>C (p.Ala705Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PP3) 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 Met: PopMAX MAF = 0.00001 in European (Non-Finnish) population in gnomAD (gnomAD v2.1.1). PP4 Met: This variant meets PM2 and is identified in 1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded (Department of Vascular Medicine, Academic Medical Center at the University of Amsterdam, Amsterdam, The Netherlands, PMID 11810272). PP3 Met: REVEL score = 0.78, which is above the threshold of 0.75.  PS3 not met: There is no functional experiment reported for this variant.  PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.2113G>T (p.Ala705Ser) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50004 · approved 2022-02-11 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/cc00e79a-6117-45c6-a00e-c5726b9419c4).*
*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 |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-05-22 |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | Pathogenic | no assertion criteria provided | research |  |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Pathogenic | no assertion criteria provided | clinical testing |  |
| ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Uncertain significance | reviewed by expert panel | curation | 2022-02-11 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | pathogenic | criteria provided, single submitter | clinical testing | 2025-07-12 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-02-26 |
| LDLR-LOVD, British Heart Foundation | Uncertain significance | criteria provided, single submitter | literature only | 2016-03-25 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2017-09-25 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-06-06 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2025-06-23 |
| Color Diagnostics, LLC DBA Color Health | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-02 |
| Clinical Genetics, Academic Medical Center | Pathogenic | no assertion criteria provided | clinical testing |  |
| All of Us Research Program, National Institutes of Health | Uncertain Significance | criteria provided, single submitter | clinical testing | 2023-12-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-08-29 |
| Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-01-30 |

## 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, not provided, Cardiovascular phenotype, Familial hypercholesterolemias, Familial hypercholesterolaemia, none provided, LDL RECEPTOR DISORDER, Hyperlipoproteinemia Type IIa, HYPER-LOW-DENSITY-LIPOPROTEINEMIA.

## Same-residue context {#hotspot}

Residue **705** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [LDLR p.Ala705Val](/variant/ldlr-p-ala705val), [LDLR p.Ala705fs](/variant/ldlr-p-ala705fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related LDLR variant pages (same residue, condition, or type): [LDLR p.Ala705Ser](/variant/ldlr-p-ala705ser), [LDLR p.Ala705Val](/variant/ldlr-p-ala705val), [LDLR p.Ala705=](/variant/ldlr-p-ala705), [LDLR p.Ala705fs](/variant/ldlr-p-ala705fs), [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 36459). 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.*