LDLR p.Ile623Val
c.1867A>G · rs555292896 · VCV252096
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PP1 BS1
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.1867A>G (p.Ile623Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1 and PP1 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: The supporting evidence is as follows: BS1: PopMax FAF= 0.002650 (0.265%) in East Asian exomes (gnomAD v2.1.1). PP1: Variant segregates with FH phenotype in 2 informative meioses in 1 family from Laboratory of Genetics and Molecular Cardiology, Brazil.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.1173 | likely benign |
|---|---|---|
| REVEL | 0.742 | pathogenic-leaning |
| SaProt | LLR -3.96 | tolerated |
| ⇒ REVEL calls this damaging; AlphaMissense and SaProt do not. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP -0.82 | GERP -4.4 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 2.528 | 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 |
|---|---|---|
| East Asiangrpmax | 0.194% | 516 |
| Remaining individualsnot grpmax-eligible | 0.0448% | 2,233 |
| Admixed American | 0.00333% | 30,001 |
| African / African-American | 0.00266% | 37,530 |
| European (non-Finnish) | 8.47e-05% | 1,180,013 |
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.Ile623Val
- Coding
- c.1867A>G
- MANE Select
- NM_000527
- dbSNP
- rs555292896
- Type
- single nucleotide variant
- Location
- chr19:11120113 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 623
- a turn
Similar variants
- LDLR p.Ile623Thr Uncertain significance ★★★ ⚠ same residue
- LDLR p.Ile623= Likely benign ★★ same residue
- LDLR p.Ile623Phe Uncertain significance ★ ⚠ same residue
- LDLR p.Ile623fs 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-ile623val (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown