LDLR p.Cys222Phe
c.665G>T · rs730882086 · VCV251362
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Likely Pathogenic for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PS4_Supporting PS3_Moderate PM1 PP3 PP4
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.665G>T (p.Cys222Phe) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM1, PM2, PS3_Moderate, PP3, PP4, PS4_Supporting 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: PM1: Variant meets PM2 and is missense in exon 4 PM2: This variant is absent from gnomAD v 2.1.1. PS3_Moderate: PMID: 24671153 Heterologous cells, 30 % cell surface LDLR and internalization PP3: REVEL is 0.971, which is greater than 0.75. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills DLCN>=6 criteria for FH from PMID 24671153, after alternative causes of high cholesterol were excluded.. PS4_Supporting: Variant meets PM2 and is identified in at least 2 unrelated index cases. 1 index case from PMID 11810272 who fulfilled unspecified clinical criteria for FH, and 1 index case from PMID 24671153 who fulfilled DLCN>6 criteria for FH.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9964 | likely pathogenic ✓ concordant with ClinVar · top 2% in LDLR |
|---|---|---|
| REVEL | 0.971 | strongly pathogenic-leaning |
| SaProt | LLR -16.77 | 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 | 28.5 | 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.Cys222Phe
- Coding
- c.665G>T
- MANE Select
- NM_000527
- dbSNP
- rs730882086
- Type
- single nucleotide variant
- Location
- chr19:11105571 (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.Cys222= Uncertain significance ★★★ 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-cys222phe (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown