Is LDLR p.Trp4fs (c.6del) pathogenic?

LDLR p.Trp4fs (c.6del) is classified Pathogenic in LDLR (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-01-16). Very rare (popmax 0.0011%, sas); Associated with Cardiovascular phenotype.

What condition is associated with LDLR p.Trp4fs (c.6del)?

LDLR p.Trp4fs (c.6del) is associated with Cardiovascular phenotype, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Trp4fs (c.6del) in the general population?

LDLR p.Trp4fs (c.6del) is very rare (popmax 0.0011%, sas) (gnomAD).

LDLR p.Trp4fs

c.6del · rs875989888 · VCV226303

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Cardiovascular phenotype

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 1 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.21	GERP 0.48, phastCons 0.92

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,002 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00048% 7/1,459,854 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,002
European (non-Finnish)	0.000509%	196,627

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.Trp4fs
Coding: c.6del
MANE Select: NM_000527
dbSNP: rs875989888
Type: Deletion
Location: chr19:11089551 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypercholesterolemia hypercholesterolemia, familial, 1

Similar variants

LDLR p.Trp4Ter Pathogenic ★★ same residue
LDLR p.Trp4_Ala13delinsArgGlyLeuGluIleAlaLeuAspArgArg 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

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-trp4fs (accessed [today's date]).

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