LDLR p.Cys352=
c.1056C>T · rs13306515 · VCV413780
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Benign for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
BP7 BP4 BA1
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.1056C>T (p.Cys352=) variant is classified as Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BA1, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025. The supporting evidence is as follows: BA1: FAF = 0.007247 (0.7%) in East Asian exomes; since FAF ≥0.5% (gnomAD v4.1.0), BA1 is met. BP4: No REVEL score. Splicing evaluation is required. Functional data on splicing not available. A) not on limits, B) it creates a GT --- MES scores: de novo donor = -3.87, authentic donor = 5.88 --- de novo score is negative, so it is not used. Variant is not predicted to alter splicing, BP4 is met. 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 carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -20 | GERP -4.9 |
| Overall | ||
| CADD | 0.675 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 0.655% | 153 |
| South Asian | 0.165% | 607 |
| Middle Eastern | 0.0825% | 1,212 |
| Ashkenazi Jewishnot grpmax-eligible | 0.0473% | 2,114 |
| Remaining individualsnot grpmax-eligible | 0.0336% | 2,976 |
| Admixed American | 0.0133% | 7,499 |
| European (non-Finnish) | 0.000678% | 147,481 |
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.Cys352=
- Coding
- c.1056C>T
- MANE Select
- NM_000527
- dbSNP
- rs13306515
- Type
- single nucleotide variant
- Location
- chr19:11110767 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 352
- the egf-like 1 domain; a UniProt-annotated variant site (in fhcl1; uncertain significance); a UniProt-annotated variant site (in fhcl1; likely pathogenic; mexico-2); a β-strand; a disulfide bond
Similar variants
- LDLR p.Cys352Tyr Likely pathogenic ★★★ same residue
- LDLR p.Cys352Arg Likely pathogenic ★★ same residue
- LDLR p.Cys352Phe Pathogenic/Likely pathogenic ★★ same residue
- LDLR p.Cys352Ser Likely pathogenic ★★ same residue
- LDLR p.Cys352Ter Pathogenic/Likely pathogenic ★★ same residue
- LDLR p.Cys352Trp Pathogenic/Likely pathogenic ★★ same residue
- LDLR p.Cys352Gly Likely pathogenic ★ same residue
- LDLR p.Cys352del Likely 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-cys352 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown