LDLR p.Ser648Pro
c.1942T>C · rs879255079 · VCV252120
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Likely Pathogenic for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PS3 PP4
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.1942T>C (p.Ser648Pro) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PM2 and PP4) 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: PS3 - 2 Level 1 assays: PMID 25386756: Heterologous cells (CHO), FACS assays - result - 50% cell surface LDLR and binding and 26% uptake. PMID 23021490: Heterologous cells (CHO), 125I-LDL and WB assays - result - 30-50% LDLR activity; reduced mature protein. ---- activity is below 70% of wild-type, so functional studies are consistent with damaging effect and PS3 is Met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PP4 - Variant meets PM2 and is identified in 1 index cases who fulfills SB possible criteria for FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, so PP4 is met.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.6599 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.604 | indeterminate |
| SaProt | LLR -9.10 | tolerated |
| ⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 5.9 | GERP 2.2, phastCons 1 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 22.5 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- LDLR
- Protein
- p.Ser648Pro
- Coding
- c.1942T>C
- MANE Select
- NM_000527
- dbSNP
- rs879255079
- Type
- single nucleotide variant
- Location
- chr19:11120188 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
Similar variants
- LDLR p.Ser648Ala Uncertain significance ★★★ ⚠ same residue
- LDLR p.Ser648Phe Uncertain significance ★★★ ⚠ same residue
- LDLR p.Ser648= Likely benign ★★ same residue
- LDLR p.Ser648fs 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-ser648pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown