LDLR p.Cys302Arg
c.904T>C · rs1555803891 · VCV440611
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PM1 PP3
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.904T>C (p.Cys302Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD version 2.1.1). PP3: REVEL = 0.972. PM1: Variant meets PM2 and alters Cys302, one of the cysteine residues listed.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9968 | likely pathogenic · top 2% in LDLR |
|---|---|---|
| REVEL | 0.972 | strongly pathogenic-leaning |
| SaProt | LLR -15.53 | 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 7.7 | GERP 1.8, phastCons 1 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 26.5 | 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
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.Cys302Arg
- Coding
- c.904T>C
- MANE Select
- NM_000527
- dbSNP
- rs1555803891
- Type
- single nucleotide variant
- Location
- chr19:11107478 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 302
- the ldl-receptor class a 7 domain; a UniProt-annotated variant site (in fhcl1); a disulfide bond
Similar variants
- LDLR p.Cys302Tyr Likely pathogenic ★★★ same residue
- LDLR p.Cys302Phe Pathogenic/Likely pathogenic ★★ same residue
- LDLR p.Cys302Trp Pathogenic/Likely pathogenic ★★ same residue
- LDLR p.Cys302fs Pathogenic/Likely pathogenic ★★ same residue
- LDLR p.Cys302Ter Pathogenic ★ same residue
- LDLR p.Cys302Gly Uncertain significance ★ ⚠ same residue
- LDLR p.Cys302Ser Uncertain significance ★ ⚠ same residue
- LDLR c.1186+5G>A 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-cys302arg (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown