Is LDLR p.Ile40fs (c.118del) pathogenic?

LDLR p.Ile40fs (c.118del) is classified Pathogenic in LDLR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-10-11). Very rare (popmax 8.48e-05%, nfe); Associated with homozygous familial hypercholesterolemia.

What condition is associated with LDLR p.Ile40fs (c.118del)?

LDLR p.Ile40fs (c.118del) is associated with homozygous familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Ile40fs (c.118del) in the general population?

LDLR p.Ile40fs (c.118del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Homozygous familial hypercholesterolemia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

LDLR p.Ile40fs

c.118del · rs879254413 · VCV251027

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

homozygous familial hypercholesterolemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 2 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.47	GERP 0.29, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,912 alleles

Overall 6.84e-05% 1/1,461,512 alleles · very rare

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.Ile40fs
Coding: c.118del
MANE Select: NM_000527
dbSNP: rs879254413
Type: Deletion
Location: chr19:11100273 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 40: a β-strand; a disulfide bond; the ldl-receptor class a 1 domain

Full LDLR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

homozygous familial hypercholesterolemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypercholesterolemia, familial, 1

For Homozygous familial hypercholesterolemia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Neonatal
Prevalence: 1-9 / 1 000 000 (Japan)

Similar variants

LDLR p.Ile40Val Uncertain significance ★★ ⚠ same residue
LDLR p.Ala612fs Likely pathogenic ★★★ same condition
LDLR p.Lys816fs Likely pathogenic ★★★ same condition
LDLR p.Tyr400_Phe402del Likely pathogenic ★★★ same condition
LDLR p.Val800fs Likely pathogenic ★★★ same condition
LDLR p.Phe86_Arg88del Uncertain significance ★★★ same condition
LDLR c.1056_1060+3del Pathogenic/Likely pathogenic ★★ same condition
LDLR c.(1060+1_1061-1 Pathogenic/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-ile40fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown