LDLR p.Ser648Phe
c.1943C>T · rs1555807266 · VCV440670
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 BP4
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.1943C>T (p.Ser648Phe) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and BP4) 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 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. BP4 - REVEL = 0.487, it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) variant not on limits B) variant is exonic and at least 50bp downstream from the canonical acceptor site, but it does not create GT. C) variant is exonic and there is an GT nearby MES scores: variant cryptic = -20.85, wt cryptic = -15.66, canonical donor = 10.28. Ratio variant cryptic/wt cryptic: -20.85/-15.66 = 1,33 --- it is above 1.1 Ratio variant cryptic/canonical donor: -20.85/10.28 --- it is not above 0.9 Variant is not predicted to alter splicing --- BP4 is Met.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.2662 | likely benign |
|---|---|---|
| REVEL | 0.379 | indeterminate |
| SaProt | LLR -6.03 | tolerated |
| ⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 3.2 | GERP 0.008, phastCons 1 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 23.2 | 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.Ser648Phe
- Coding
- c.1943C>T
- MANE Select
- NM_000527
- dbSNP
- rs1555807266
- Type
- single nucleotide variant
- Location
- chr19:11120189 (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.Ser648Pro Likely pathogenic ★★★ ⚠ same residue
- LDLR p.Ser648Ala 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-ser648phe (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown