LDLR p.Arg253Pro
c.758G>C · rs139507589 · VCV251435
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PP3 PP4
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.758G>C (p.Arg253Pro) variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying evidence PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (v2.1.1). PP3 - REVEL = 0.77, which is above the threshold of 0.75. PP4 - Variant meets PM2 and was identified in 1 index case with Simon Broome criteria for FH (PMID: 20236128) after alternative causes of cholesterol were excluded. Note: two other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.757C>T (p.Arg253Trp); 2) NM_000527.5(LDLR):c.758G>A (p.Arg253Gln); however, both are VUS by these LDLR guidelines (PM5 not applicable).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9272 | likely pathogenic |
|---|---|---|
| REVEL | 0.773 | moderately pathogenic-leaning |
| SaProt | LLR -13.69 | 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 0.8 | GERP 0.65, phastCons 0.78 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 24.1 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- LDLR
- Protein
- p.Arg253Pro
- Coding
- c.758G>C
- MANE Select
- NM_000527
- dbSNP
- rs139507589
- Type
- single nucleotide variant
- Location
- chr19:11106628 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 253
- the ldl-receptor class a 6 domain; a UniProt-annotated variant site (in fhcl1; uncertain significance); an α-helix
Similar variants
- LDLR p.Arg253Gln Uncertain significance ★★★ ⚠ same residue
- LDLR p.Arg253Trp Uncertain significance ★★★ ⚠ same residue
- LDLR p.Arg253Gly Uncertain significance ★ ⚠ same residue
- LDLR p.Arg253= 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
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-arg253pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown