LDLR p.Ala684Val
c.2051C>T · rs1258914809 · VCV1785078
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PP3
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.2051C>T (p.Ala684Val) variant is classified as Uncertain Significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 20 February 2025. The supporting evidence is as follows: PM2: PopMax MAF=00001667 (0.001667%) in Admixed American exomes+genomes (gnomAD v4.1.0). PP3: REVEL score = 0.787.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.5473 | ambiguous |
|---|---|---|
| REVEL | 0.787 | moderately pathogenic-leaning |
| SaProt | LLR -10.70 | damaging |
| ⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 7.5 | GERP 2.5, phastCons 1 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 27.5 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.00167% | 59,996 |
| African / African-American | 0.00133% | 74,950 |
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.Ala684Val
- Coding
- c.2051C>T
- MANE Select
- NM_000527
- dbSNP
- rs1258914809
- Type
- single nucleotide variant
- Location
- chr19:11120433 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 684
- the egf-like 3 domain
Similar variants
- LDLR p.Ala684Pro Uncertain significance ★★★ ⚠ same residue
- LDLR p.Ala684Thr Uncertain significance ★★★ ⚠ same residue
- LDLR p.Ala684= Likely benign ★★ same residue
- LDLR p.Ala684fs 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-ala684val (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown