LDLR p.Val613Ile
c.1837G>A · rs148181903 · VCV161288
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PS4_Supporting PP4
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.1837G>A (p.Val613Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PS4_Supporting and PP4 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 as follows: PM2: PopMax MAF = 0.00005340 (0.005%) in African/African American exomes+genomes (gnomAD v4.1.0). PS4_Supporting, PP4: Variant meets PM2 and is identified in 2 unrelated index cases meeting FH criteria (1 case in PMID 19837725 (Whittall et al., 2010), UK; 1 case in PMID 16250003 (Fouchier et al., 2005), Netherlands).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.0785 | likely benign |
|---|---|---|
| REVEL | 0.564 | indeterminate |
| SaProt | LLR -7.91 | tolerated |
| ⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP -0.66 | GERP 0.28 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 10.71 | 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 |
|---|---|---|
| African / African-Americangrpmax | 0.00534% | 18,728 |
| Admixed American | 0.00334% | 29,980 |
| European (non-Finnish) | 0.00288% | 34,707 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,480 |
| South Asian | 0.0011% | 91,094 |
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.Val613Ile
- Coding
- c.1837G>A
- MANE Select
- NM_000527
- dbSNP
- rs148181903
- Type
- single nucleotide variant
- Location
- chr19:11116990 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 613
- a β-strand
Similar variants
- LDLR p.Val613Phe Uncertain significance ★ ⚠ same residue
- LDLR p.Val613= Likely benign ★ same residue
- LDLR p.Val613_Phe614insTer Pathogenic ★ same residue
- LDLR p.Val613fs 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-val613ile (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown