LDLR p.Phe614Ile
c.1840T>A · rs879255043 · VCV252061
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Likely Pathogenic for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PS3 PP1 PP3 PP4
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.1840T>A (p.Phe614Ile) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PM2, PP1, PP3 and PP4 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: This variant is absent from gnomAD (gnomAD v4.1.0). PP3: REVEL=0.912. PS3: Level 1 assays: PMID 35568682 (Graça et al., 2022): Heterologous cells (CHO-ldlA7 cells), cytometry assays - results - <60% surface LDLR, <60% LDL-LDLR binding, <60% uptake. ---- results are below 70% of wild-type, so functional study is consistent with damaging effect. PP4: Variant meets PM2 and is identified in 1 case with Possible FH by Simon Broome criteria from Cardiovascular Research group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal, after alternative causes of high cholesterol were excluded. PP1: Variant segregates with FH phenotype in 2 informative meioses identified by Cardiovascular Research group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9097 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.912 | moderately pathogenic-leaning |
| SaProt | LLR -13.93 | 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 7.7 | GERP 2.3, phastCons 1 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic |
| Overall | ||
| CADD | 26.8 | 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.Phe614Ile
- Coding
- c.1840T>A
- MANE Select
- NM_000527
- dbSNP
- rs879255043
- Type
- single nucleotide variant
- Location
- chr19:11116993 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 614
- a β-strand
Similar variants
- LDLR p.Phe614Val Uncertain significance ★ ⚠ 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
- LDLR c.2389+2T>G 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-phe614ile (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown