LDLR p.Asp415Val
c.1244A>T · rs879254845 · VCV251750
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PP3 PM3
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.1244A>T (p.Asp415Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM3 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.929. PM3: 1 case reported in PMID 36325061 (Du et al., 2022), China, who was homozygous and presented with an untreated LDL-C ≥13 mmol/L or a treated LDL-C ≥8 mmol/L and either cutaneous or tendon xanthomas before the age of 10 years.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.5156 | ambiguous |
|---|---|---|
| REVEL | 0.929 | moderately pathogenic-leaning |
| SaProt | LLR -11.12 | damaging |
| ⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 6 | GERP 1.5, phastCons 1 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 22.9 | 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.Asp415Val
- Coding
- c.1244A>T
- MANE Select
- NM_000527
- dbSNP
- rs879254845
- Type
- single nucleotide variant
- Location
- chr19:11113335 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 415
- a UniProt-annotated variant site (in fhcl1; uncertain significance)
Similar variants
- LDLR p.Asp415Gly Likely pathogenic ★★★ ⚠ same residue
- LDLR p.Asp415His Likely pathogenic ★★★ ⚠ same residue
- LDLR p.Asp415Glu Uncertain significance ★ ⚠ same residue
- LDLR p.Asp415fs Pathogenic ★★ 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-asp415val (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown