# NM_000527.5(LDLR):c.267C>T (p.Cys89=)

https://sugi.bio/variant/ldlr-p-cys89

## Summary

**LDLR p.Cys89= (c.267C>T)** is classified **Likely benign** in LDLR (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-11-13). Ultra-rare (popmax 0.02%, afr); Associated with Cardiovascular phenotype.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs777640882 · 6 submitters · 3 linked conditions · ultra-rare (popmax 0.02%, afr)

## For patients & families {#patients}

This is a change in the LDLR gene that is classified as likely benign — not considered disease-causing, submitted by 6 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.Cys89= |
| Coding change (HGVS c.) | c.267C>T |
| MANE Select transcript | [NM_000527](https://www.ncbi.nlm.nih.gov/nuccore/NM_000527) |
| dbSNP | [rs777640882](https://www.ncbi.nlm.nih.gov/snp/rs777640882/) |
| Variant type | single nucleotide variant |
| Location | chr19:11102740-11102740 (GRCh38) |
| ClinVar | [VCV496024](https://www.ncbi.nlm.nih.gov/clinvar/variation/496024/) |

**All HGVS expressions:** `LRG_274:g.18360C>T`, `LRG_274t1:c.267C>T`, `NC_000019.10:g.11102740C>T`, `NC_000019.9:g.11213416C>T`, `NG_009060.1:g.18360C>T`, `NM_000527.5:c.267C>T`, `NM_001195798.2:c.267C>T`, `NM_001195799.2:c.190+2395C>T`, `NM_001195800.2:c.267C>T`, `NM_001195803.2:c.267C>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 -3.103, GERP -5.06 — fast-evolving / accelerated position
- CADD: **PHRED 3.195**. 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). 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. This allele is not in the release, so all four of its deltas are under 0.2. 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, and here that is proven rather than inferred: a different substitution at this very position, C>A, IS in the release and scores Δ0.35 donor gain, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *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 **0.02%** (afr) · FAF95 0.0123% · FAF99 0.00989% · 15/74,912 in the highest group · 20/1,613,794 alleles overall — ultra-rare (popmax 0.02%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.02% | 4,994 |
| South Asian | 0.0011% | 91,084 |
| European (non-Finnish) | 0.000339% | 294,974 |

*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 **89** lies in a disulfide bond; the ldl-receptor class a 2 domain; a UniProt-annotated variant site (in fhcl1).

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.Cys89= falls in the ldl-receptor class a 2 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-11-13.

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

**Submission history:** 6 submissions (2017–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2019-08-28 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2017-09-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-08-22 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2023-12-18 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-09-05 |
| GENinCode PLC | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-13 |

## 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, not specified, Familial hypercholesterolemia, Hypercholesterolemia, familial, 1, LDL RECEPTOR DISORDER, Hyperlipoproteinemia Type IIa, HYPER-LOW-DENSITY-LIPOPROTEINEMIA, HYPERCHOLESTEROLEMIC XANTHOMATOSIS, FAMILIAL, Fredrickson type IIa hyperlipoproteinemia, Hyperlipoproteinemia type 2.

## Same-residue context {#hotspot}

Residue **89** carries **4 other pathogenic ClinVar variants** — a recurrently-mutated position: [LDLR p.Cys89Tyr](/variant/ldlr-p-cys89tyr), [LDLR p.Cys89Arg](/variant/ldlr-p-cys89arg), [LDLR p.Cys89Gly](/variant/ldlr-p-cys89gly), [LDLR p.Cys89Trp](/variant/ldlr-p-cys89trp). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related LDLR variant pages (same residue, condition, or type): [LDLR p.Cys89Arg](/variant/ldlr-p-cys89arg), [LDLR p.Cys89Gly](/variant/ldlr-p-cys89gly), [LDLR p.Cys89Trp](/variant/ldlr-p-cys89trp), [LDLR p.Cys89Tyr](/variant/ldlr-p-cys89tyr), [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 496024). 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.*