LDLR p.Trp443Ser
c.1328G>C · rs879254866 · VCV251790
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Likely Pathogenic for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PS4_Moderate PP3 PP4 PM5
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.1328G>C (p.Trp443Ser) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PS4_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.0000006841 (0.00006841 %) in European (non-Finnish) exomes (gnomAD version 4.1.0). PP3: REVEL = 0.934. PM5: 1 other missense variant in the same codon: NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys) (ClinVar ID 251792)- Pathogenic by these guidelines. PS4_Moderate, PP4: Variant meets PM2 and is identified in at least 9 unrelated index cases who fulfill criteria for FH: 1 case meeting Simon Broome criteria from PMID 17142622 (Humphries et al., 2006), UK; 1 case meeting Simon Broome possible FH criteria 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; 3 cases with DLCN >=6 from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, France; 4 cases with DLCN >=6 from PMID 34871818 (Tada et al., 2022), Japan.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9666 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.934 | strongly pathogenic-leaning |
| SaProt | LLR -14.29 | 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 12 | GERP 2.5, phastCons 1 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 32.0 | 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.Trp443Ser
- Coding
- c.1328G>C
- MANE Select
- NM_000527
- dbSNP
- rs879254866
- Type
- single nucleotide variant
- Location
- chr19:11113419 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 443
- a UniProt-annotated variant site (in fhcl1; north platt); a β-strand
Similar variants
- LDLR p.Trp443Arg Likely pathogenic ★★★ same residue
- LDLR p.Trp443Cys Pathogenic ★★★ same residue
- LDLR p.Trp443Ter 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-trp443ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown