LDLR p.Cys243Arg
c.727T>C · rs879254659 · VCV251425
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Likely Pathogenic for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PS4_Supporting PM1 PP3 PP4
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.727T>C (p.Cys243Arg) variant is classified as likely pathogenic for Familial Hypercholesterolemia by applying evidence code PM1, PM2, PP3, PP4 and PS4_Supporting 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 - This variant is absent from gnomAD (gnomAD v2.1.1). PP3 - REVEL = 0.966 PM1 - Variant meets PM2 and alters Cys243, one of the cysteine residues listed. PS4_Supporting - Variant meets PM2 and is identified in 2 index cases who fullfill DLCN≥6 criteria for FH from Research Lab of Molecular Genetics of Lipid Metabolism and PMID: 28502510. PP4 - Variant meets PM2 and is identified in 2 index cases who fullfill DLCN≥6 criteria for FH from Research Lab of Molecular Genetics of Lipid Metabolism after alternative cause of high cholesterol were excluded.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9959 | likely pathogenic ✓ concordant with ClinVar · top 3% in LDLR |
|---|---|---|
| REVEL | 0.966 | strongly pathogenic-leaning |
| SaProt | LLR -13.81 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 7.8 | GERP 1.9, phastCons 1 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 26.4 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- LDLR
- Protein
- p.Cys243Arg
- Coding
- c.727T>C
- MANE Select
- NM_000527
- dbSNP
- rs879254659
- Type
- single nucleotide variant
- Location
- chr19:11106597 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 243
- the ldl-receptor class a 6 domain; a UniProt-annotated variant site (in fhcl1; likely pathogenic); a β-strand; a disulfide bond
Similar variants
- LDLR p.Cys243= Likely benign ★★ same residue
- LDLR p.Cys243Ser Likely pathogenic ★ same residue
- LDLR c.1186+5G>A Likely pathogenic ★★★ same condition
- LDLR c.1359-1G>A Pathogenic ★★★ same condition
- LDLR c.1359-5C>G Likely pathogenic ★★★ same condition
- LDLR c.1705+2T>C Likely pathogenic ★★★ same condition
- LDLR c.190+4A>T Likely pathogenic ★★★ same condition
- LDLR c.2140+1G>A Pathogenic ★★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ldlr-p-cys243arg (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown