LDLR p.Phe530Val
c.1588T>G · rs875989924 · VCV226361
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PS4_Supporting PP3 PP4
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.1588T>G (p.Phe530Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PS4_Supporting, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 20 February 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.00001891 (0.001891%) in European (non-Finnish) exomes/genomes (gnomAD v4.1.0). PP3: REVEL = 0.868. PS4_Supporting, PP4: Variant meets PM2 and is identified in 2 unrelated index cases (1 case with DLCN>=6 from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia; 1 case fulfilling Japan Atherosclerosis Society criteria for FH reported in PMID 36229376 (Tada et al., 2022)), after alternative causes of high cholesterol were excluded.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.6371 | likely pathogenic |
|---|---|---|
| REVEL | 0.868 | moderately pathogenic-leaning |
| SaProt | LLR -13.58 | 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 2.5, phastCons 1 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 29.0 | 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 |
|---|---|---|
| European (non-Finnish)grpmax | 0.00189% | 52,887 |
| Remaining individualsnot grpmax-eligible | 0.00162% | 61,854 |
| African / African-American | 0.00134% | 74,448 |
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.Phe530Val
- Coding
- c.1588T>G
- MANE Select
- NM_000527
- dbSNP
- rs875989924
- Type
- single nucleotide variant
- Location
- chr19:11116095 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 530
- a β-strand
Similar variants
- LDLR p.Phe530Leu Uncertain significance ★★★ ⚠ same residue
- LDLR p.Phe530= Likely benign ★ same residue
- LDLR p.Phe530fs 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-phe530val (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown