LDLR p.Ala705Pro
c.2113G>C · rs193922570 · VCV36459
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PP3 PP4
Curation rationale (ClinGen, verbatim)
The NM_000527.5 (LDLR): c.2113G>C (p.Ala705Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 Met: PopMAX MAF = 0.00001 in European (Non-Finnish) population in gnomAD (gnomAD v2.1.1). PP4 Met: This variant meets PM2 and is identified in 1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded (Department of Vascular Medicine, Academic Medical Center at the University of Amsterdam, Amsterdam, The Netherlands, PMID 11810272). PP3 Met: REVEL score = 0.78, which is above the threshold of 0.75. PS3 not met: There is no functional experiment reported for this variant. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.2113G>T (p.Ala705Ser) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.7084 | likely pathogenic |
|---|---|---|
| REVEL | 0.78 | moderately pathogenic-leaning |
| SaProt | LLR -12.40 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 8.4 | GERP 1.2, phastCons 1 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 23.7 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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.Ala705Pro
- Coding
- c.2113G>C
- MANE Select
- NM_000527
- dbSNP
- rs193922570
- Type
- single nucleotide variant
- Location
- chr19:11120495 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 705
- the egf-like 3 domain
Similar variants
- LDLR p.Ala705Ser Uncertain significance ★★★ ⚠ same residue
- LDLR p.Ala705Val Likely pathogenic ★ same residue
- LDLR p.Ala705= Likely benign ★ same residue
- LDLR p.Ala705fs 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-ala705pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown