LDLR p.Arg81Ser
c.241C>A · rs730882078 · VCV251088
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PP4
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR): c.241C>A (p.Arg81Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP4 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 (v2.1.1). PP4 - Variant meet PM2. PMID: 21382890 (Graaf et al., 2011) - 1 case with LDL-C level >95th percentile for age and gender and autosomal dominant inheritance pattern of hypercholesterolemia, ie, at least 1 biological parent on treatment for hypercholesterolemia and a family history of hypercholesterolemia and cardiovascular disease. Alternative causes of high cholesterol were excluded.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.3928 | ambiguous |
|---|---|---|
| REVEL | 0.669 | pathogenic-leaning |
| SaProt | LLR -6.17 | tolerated |
| ⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 5.8 | GERP 2.5, phastCons 1 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 27.4 | 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.Arg81Ser
- Coding
- c.241C>A
- MANE Select
- NM_000527
- dbSNP
- rs730882078
- Type
- single nucleotide variant
- Location
- chr19:11102714 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 81
- a disulfide bond; the ldl-receptor class a 2 domain
Similar variants
- LDLR p.Arg81Cys Likely pathogenic ★★★ same residue
- LDLR p.Arg81His Uncertain significance ★★★ ⚠ same residue
- LDLR p.Arg81Leu 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
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-arg81ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown