LDLR p.Val775Ala
c.2324T>C · rs780300776 · VCV440691
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 BP4
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.2324T>C (p.Val775Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025. The supporting evidence is follows: PM2: PopMax MAF = 0.00002627 (0.0026%) in European (non-Finnish) exomes+genomes (gnomAD v4.1.0). BP4: REVEL=0.244. It is below 0.5, so splicing evaluation is required. A) not on limits B) does not create AG C) there is an AG nearby. MES scores: variant cryptic = 1.45, wt cryptic = 2.52, canonical acceptor = 11.36. Ratio variant cryptic/wt cryptic: 0.57 --- it is below 1.1. Ratio variant cryptic/canonical acceptor: 0.12--- it is below 0.9. Variant is not predicted to alter splicing.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.0722 | likely benign |
|---|---|---|
| REVEL | 0.244 | benign-leaning |
| SaProt | LLR -5.90 | tolerated |
| ⇒ AlphaMissense, REVEL and SaProt all call this tolerated. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP -3.7 | GERP -2.8 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 0.104 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.00263% | 38,065 |
| Finnishnot grpmax-eligible | 0.00156% | 64,016 |
| African / African-American | 0.00134% | 74,896 |
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.Val775Ala
- Coding
- c.2324T>C
- MANE Select
- NM_000527
- dbSNP
- rs780300776
- Type
- single nucleotide variant
- Location
- chr19:11128020 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
Similar variants
- LDLR p.Val775Ile Uncertain significance ★★★ ⚠ same residue
- LDLR p.Val775Phe Uncertain significance ★ ⚠ same residue
- LDLR p.Val775_Pro784del Pathogenic ★ same residue
- LDLR p.Val775= 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-val775ala (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown