LDLR p.Ser673Arg
c.2017A>C · rs749085746 · VCV252172
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.2017A>C (p.Ser673Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 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= 0.0000008474 (0.00008474%) in European non-Finnish exomes + genomes (gnomAD v.4.1.0).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.1688 | likely benign |
|---|---|---|
| REVEL | 0.504 | indeterminate |
| SaProt | LLR -4.59 | tolerated |
| ⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 1.4 | GERP -0.82, phastCons 0.001 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 5.885 | 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
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.Ser673Arg
- Coding
- c.2017A>C
- MANE Select
- NM_000527
- dbSNP
- rs749085746
- Type
- single nucleotide variant
- Location
- chr19:11120399 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 673
- the egf-like 3 domain; an α-helix
Similar variants
- LDLR p.Ser673Asn Uncertain significance ★★★ ⚠ same residue
- LDLR p.Ser673= 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
- LDLR c.190+4A>T Likely pathogenic ★★★ same condition
- LDLR c.2140+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-ser673arg (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown