LDLR p.Asp304Val
c.911A>T · rs1555803898 · VCV440613
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PP3 PM5
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.911A>T (p.Asp304Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PM5 and PP3 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 (gnomAD v2.1.1), so PM2 is Met. PM5 - 4 other missense variants in the same codon: - NNM_000527.5(LDLR):c.910G>A (p.Asp304Asn) (ClinVar ID 3692) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.910G>C (p.Asp304His) (ClinVar ID 440612) - VUS by these guidelines - NM_000527.5(LDLR):c.912C>G (p.Asp304Glu) (ClinVar ID 226336) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr) (ClinVar ID 251517) - Likely pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met. PP3 - REVEL = 0.985. It is above 0.75, so PP3 is Met.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9849 | likely pathogenic · top 8% in LDLR |
|---|---|---|
| REVEL | 0.985 | strongly pathogenic-leaning |
| SaProt | LLR -15.87 | 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 11 | GERP 1.8, phastCons 1 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 26.3 | 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.Asp304Val
- Coding
- c.911A>T
- MANE Select
- NM_000527
- dbSNP
- rs1555803898
- Type
- single nucleotide variant
- Location
- chr19:11107485 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 304
- the ldl-receptor class a 7 domain; a UniProt-annotated variant site (in fhcl1; likely pathogenic; baltimore-1); a UniProt-annotated variant site (in fhcl1; pathogenic; denver-2)
Similar variants
- LDLR p.Asp304Asn Pathogenic ★★★ same residue
- LDLR p.Asp304Glu Likely pathogenic ★★★ same residue
- LDLR p.Asp304Tyr Likely pathogenic ★★★ same residue
- LDLR p.Asp304His Uncertain significance ★★★ ⚠ same residue
- LDLR p.Asp304= Likely benign ★ same residue
- LDLR p.Asp304fs 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-asp304val (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown