LDLR p.Phe403del
c.1204TTC[1] · rs879254830 · VCV251731
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Likely Pathogenic for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PS4_Supporting PP4 PM4
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.1207_1209del (p.Phe403del) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM4, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (v2.1.1). PM4: Variant meets PM2 and is an in-frame deletion. PS4_Supporting, PP4: Variant meets PM2 and was identified in at least 5 unrelated index cases who fulfill criteria for FH (4 patients from PMID 22698793 (Tichý et al., 2012) and 1 patient from PMID 11462246 (Nauck et al., 2001), reported as 1205delTCT).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 5.9 | GERP 2.1, phastCons 1 |
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.Phe403del
- Coding
- c.1204TTC[1]
- MANE Select
- NM_000527
- dbSNP
- rs879254830
- Type
- Microsatellite
- Location
- chr19:11113293 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 403
- a UniProt-annotated variant site (in fhcl1); a β-strand
Similar variants
- LDLR p.Phe403= Likely benign ★★ same residue
- LDLR p.Phe403fs Pathogenic ★ same residue
- LDLR p.Phe403Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
- LDLR p.Gly219del Pathogenic ★★★ same condition
- LDLR c.190+2_190+3del Likely pathogenic ★★ same condition
- LDLR p.Arg124fs Pathogenic ★★ same condition
- LDLR p.Arg458fs Pathogenic ★★ same condition
- LDLR p.Asn322del Pathogenic/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-phe403del (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown