LDLR p.Ala166=
c.498C>T · rs10417394 · VCV328050
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Likely Benign for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
BS1 BP7 BP4
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.498C>T (p.Ala166=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (spcification version 1.2) on 30 August 2024. The supporting evidence is as follows: BS1: FAF=0.004221 (0.42%) in African/African American exomes + genomes (gnomAD v4.1.0). BP4: No REVEL, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) does not create a GT. C) there is a GT nearby. MES scores: variant cryptic = -2.92, wt cryptic = -2.92, canonical donor = 7.67. Cryptic scores are negative, so cryptic site is not used - 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 carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 0.19 | GERP -5.1, phastCons 0.028 |
| Overall | ||
| CADD | 5.279 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.462% | 216 |
| Middle Eastern | 0.0495% | 2,021 |
| Remaining individualsnot grpmax-eligible | 0.04% | 2,500 |
| Admixed American | 0.0383% | 2,610 |
| South Asian | 0.00329% | 30,363 |
| European (non-Finnish) | 8.47e-05% | 1,180,008 |
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.Ala166=
- Coding
- c.498C>T
- MANE Select
- NM_000527
- dbSNP
- rs10417394
- Type
- single nucleotide variant
- Location
- chr19:11105404 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 166
- the 'binding to getah virus e1-e2 spike glycoproteins' region; a disulfide bond; the ldl-receptor class a 4 domain
Similar variants
- LDLR p.Ala166Asp Uncertain significance ★★ ⚠ same residue
- LDLR p.Ala166Thr Uncertain significance ★★ ⚠ same residue
- LDLR p.Ala166Val Uncertain significance ★★ ⚠ same residue
- LDLR p.Ala166Pro Uncertain significance ★ ⚠ 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
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-ala166 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown