LDLR p.Arg427=
c.1279A>C · rs371355878 · VCV251764
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Likely Benign for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PP4 BP7 BP4 BP2
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.1279A>C (p.Arg427=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BP2, BP4, BP7, PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00006976 (0.006976%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1). BP4: No REVEL, splicing evaluation required. Functional data on splicing not available. A) variant not on limits B) does not create AG/GT C) variant is exonic and there is no AG/GT nearby Variant is not predicted to alter splicing. --- BP4 is met. BP7: Variant is synonymous and meets BP4. BP2: Variant identified in an index case with heterozygous FH phenotype (LDL-C=170mg/dL on statins) and LDLR c.530C>T (p.Ser177Leu) (confirmed in trans), classified as Pathogenic by these guidelines, from Cardiovascular Research Group, Instituto Nacional de Saúde Dr. Ricardo Jorge, Portugal. PP4: Variant meets PM2 and is identified in 1 index case with possible FH by Simon Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saúde Dr. Ricardo Jorge, Portugal. Variant has 3 Supporting evidence codes towards Benign, enough to classify as Likely Benign and only 1 Moderate plus 1 Supporting evidence codes towards Pathogenic, so we are confident in classifying this variant as Likely Benign.
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 9.1 | GERP 1.5, phastCons 1 |
| Overall | ||
| CADD | 12.33 | 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.Arg427=
- Coding
- c.1279A>C
- MANE Select
- NM_000527
- dbSNP
- rs371355878
- Type
- single nucleotide variant
- Location
- chr19:11113370 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 427
- a β-strand
Similar variants
- LDLR p.Arg427Lys Likely benign ★ 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
- LDLR c.190+4A>T Likely pathogenic ★★★ same condition
- LDLR c.2140+1G>A Pathogenic ★★★ same condition
- LDLR c.2389+2T>G 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-arg427 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown