LDLR p.Cys222=
c.666C>T · rs756613387 · VCV440592
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 BP7 BP4
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.666C>T (p.Cys222=) variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, BP4, BP7) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: - PM2: PopMax MAF = 0.000008864 (0.0008864%) in European (non-Finnish) exomes (gnomAD v2.1.1). - BP4: No REVEL, splicing evaluation required. Functional data on splicing not available. B) variant is exonic and at least 50bp downstream from canonical acceptor site and creates GT MES scores: de novo variant = 5.19; canonical donor = 7.67. Ratio de novo variant/canonical donor = 5.19/7.67 = 0.67 --- it is below 0.8 Variant is not predicted to alter splicing. - BP7: Variant is synonymous and meets BP4.
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/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.74 | donor gain · deltas |
|---|---|---|
| Pangolin | Δ0.31 | gain · loss 0.07 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP 5.8 | GERP 2.5, phastCons 1 |
| Overall | ||
| CADD | 21.7 | PHRED · no single calibrated threshold — expert panels disagree |
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.Cys222=
- Coding
- c.666C>T
- MANE Select
- NM_000527
- dbSNP
- rs756613387
- Type
- single nucleotide variant
- Location
- chr19:11105572 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 222
- a UniProt-annotated variant site (in fhcl1; likely pathogenic); the 'binding to getah virus e1-e2 spike glycoproteins' region; a β-strand; a disulfide bond; the ldl-receptor class a 5 domain
Similar variants
- LDLR p.Cys222Arg Likely pathogenic ★★★ same residue
- LDLR p.Cys222Phe Likely pathogenic ★★★ same residue
- LDLR p.Cys222Gly Likely pathogenic ★★ same residue
- LDLR p.Cys222Ter Pathogenic ★★ same residue
- LDLR p.Cys222Trp Likely pathogenic ★★ same residue
- LDLR p.Cys222Tyr Pathogenic/Likely pathogenic ★★ same residue
- LDLR p.Cys222_Asp227delinsTer Pathogenic ★★ same residue
- LDLR p.Cys222_Asn230delinsTer Pathogenic ★ same residue
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-cys222 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown