LDLR p.Ser587Arg
c.1761C>G · rs753430282 · VCV252021
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.1761C>G (p.Ser587Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.00001356 (0.0014%) in European (non-Finnish) (gnomAD v4.1.0).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9393 | likely pathogenic |
|---|---|---|
| REVEL | 0.746 | pathogenic-leaning |
| SaProt | LLR -10.63 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | Δ0.28 | acceptor gain · deltas |
| Constraint at this position | ||
| Conservation | phyloP 0.062 | GERP -2.9, phastCons 0.071 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 21.8 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,484 |
| European (non-Finnish)grpmax | 0.00136% | 73,746 |
Remaining individuals shows a higher raw frequency than the grpmax group above it. 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.
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- LDLR
- Protein
- p.Ser587Arg
- Coding
- c.1761C>G
- MANE Select
- NM_000527
- dbSNP
- rs753430282
- Type
- single nucleotide variant
- Location
- chr19:11116914 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 587
- a β-strand
Similar variants
- LDLR p.Ser587= Likely benign ★★ same residue
- LDLR p.Ser587fs 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-ser587arg (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown