LDLR p.Asp307Asn
c.919G>A · rs879254719 · VCV251525
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Likely Pathogenic for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PP1_Moderate PS4_Moderate PP3 PP4
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.919G>A (p.Asp307Asn) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PP1_Moderate, PM2, PS4_Moderate, PP3 and PP4 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: PP1_Moderate: Variant segregates with FH phenotype in at least 5 informative meiosis from 2 different families (PMID: 32706999, Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)). PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PS4_Moderate:Variant meets PM2 and is identified in at least 6 unrelated index cases who fulfill SB possible or definite criteria for FH from different labs (PMID: 32706999, Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation). PP3: REVEL = 0.865 PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills SB definite FH after alternative causes of high cholesterol were excluded (PMID: 32706999).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.979 | likely pathogenic · top 10% in LDLR |
|---|---|---|
| REVEL | 0.865 | moderately pathogenic-leaning |
| SaProt | LLR -10.80 | 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 1.8, phastCons 1 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 29.0 | PHRED · no single calibrated threshold — expert panels disagree |
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.Asp307Asn
- Coding
- c.919G>A
- MANE Select
- NM_000527
- dbSNP
- rs879254719
- Type
- single nucleotide variant
- Location
- chr19:11107493 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 307
- the ldl-receptor class a 7 domain; a β-strand
Similar variants
- LDLR p.Asp307Glu Pathogenic/Likely pathogenic ★★ same residue
- LDLR p.Asp307Gly Pathogenic/Likely pathogenic ★★ same residue
- LDLR p.Asp307His Likely pathogenic ★★ same residue
- LDLR p.Asp307Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
- LDLR p.Asp307Tyr Uncertain significance ★ ⚠ same residue
- LDLR p.Asp307fs Pathogenic ★★ same residue
- LDLR c.1186+5G>A Likely pathogenic ★★★ same condition
- LDLR c.1359-1G>A 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-asp307asn (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown