# NM_000527.5(LDLR):c.2358C>T (p.Ser786=)

https://sugi.bio/variant/ldlr-p-ser786

## Summary

**LDLR p.Ser786= (c.2358C>T)** is classified **Conflicting classifications of pathogenicity** in LDLR (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-31). Rare (popmax 0.194%, eas); Associated with hypercholesterolemia, familial, 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs183255090 · 9 submitters · 2 linked conditions · rare (popmax 0.194%, eas)

## For patients & families {#patients}

This is a change in the LDLR gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 9 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.Ser786= |
| Coding change (HGVS c.) | c.2358C>T |
| MANE Select transcript | [NM_000527](https://www.ncbi.nlm.nih.gov/nuccore/NM_000527) |
| dbSNP | [rs183255090](https://www.ncbi.nlm.nih.gov/snp/rs183255090/) |
| Variant type | single nucleotide variant |
| Location | chr19:11128054-11128054 (GRCh38) |
| ClinVar | [VCV491665](https://www.ncbi.nlm.nih.gov/clinvar/variation/491665/) |

**All HGVS expressions:** `LRG_274:g.43674C>T`, `LRG_274t1:c.2358C>T`, `NC_000019.10:g.11128054C>T`, `NC_000019.9:g.11238730C>T`, `NG_009060.1:g.43674C>T`, `NM_000527.5:c.2358C>T`, `NM_001195798.2:c.2358C>T`, `NM_001195799.2:c.2235C>T`, `NM_001195800.2:c.1854C>T`, `NM_001195803.2:c.1824C>T`

## 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 -5.182, GERP -2.78 — fast-evolving / accelerated position
- CADD: **PHRED 1.952**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.59 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.194%** (eas) · FAF95 0.161% · FAF99 0.149% · 87/44,874 in the highest group · 160/1,614,108 alleles overall — rare (popmax 0.194%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.194% | 516 |
| South Asian | 0.0549% | 1,822 |
| Remaining individuals (not grpmax-eligible) | 0.0288% | 3,473 |
| African / African-American | 0.00267% | 37,516 |
| European (non-Finnish) | 0.000254% | 393,334 |

*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}


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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-31.

**Submitter consensus:** conflicting (5 Likely benign, 2 Benign, 1 Uncertain significance, 1 Likely Benign).

**Submission history:** 9 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2020-07-19 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Benign | criteria provided, single submitter | clinical testing | 2021-04-10 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2017-10-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-31 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2024-02-05 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-08-22 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-10-28 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-23 |

## 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, not specified, Cardiovascular phenotype, LDLR-related disorder, LDLR-related condition, none provided, LDL RECEPTOR DISORDER, Hyperlipoproteinemia Type IIa.

## Similar variants {#similar}

Related LDLR variant pages (same residue, condition, or type): [LDLR p.Ser786Cys](/variant/ldlr-p-ser786cys), [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 491665). 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.*