LDLR p.Leu599Ser
c.1796T>C · rs879255025 · VCV252035
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Likely Pathogenic for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PS4_Moderate PP3 PP4
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.1796T>C (p.Leu599Ser) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PS4_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 22 July 2022. The supporting evidence is as follows: PM2: Variant is absent from gnomAD v2.1.1. PP3: REVEL = 0.779. PS4, PP4: Variant meets PM2 and is identified in 9 unrelated index cases fulfilling FH clinical criteria (5 cases with DLCN score ≥6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 1 meeting Simon Broome criteria from PMID 12436241 (Amsellem et al., 2002), APHP Saint Antoine Hospital, Paris, France; 1 meeting Simon Broome criteria from PMID 17094996 (Tosi et al., 2007), UK; 1 with DLCN score ≥6 from PMID 19318025 (Alonso et al., 2009), Spain; and 1 with DLCN score ≥6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, France).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.691 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.779 | moderately pathogenic-leaning |
| SaProt | LLR -13.59 | 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 6 | GERP 2.3, phastCons 1 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 24.8 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
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.Leu599Ser
- Coding
- c.1796T>C
- MANE Select
- NM_000527
- dbSNP
- rs879255025
- Type
- single nucleotide variant
- Location
- chr19:11116949 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 599
- a UniProt-annotated variant site (in fhcl1; uncertain significance; london-5); a β-strand
Similar variants
- LDLR p.Leu599Trp Uncertain significance ★★★ ⚠ same residue
- LDLR p.Leu599= Likely benign ★ same residue
- LDLR p.Leu599fs Pathogenic/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-leu599ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown