Is LDLR p.Pro181Ter (c.541_542delinsTA) pathogenic?

LDLR p.Pro181Ter (c.541542delinsTA) is classified Pathogenic in LDLR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-07). Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Pro181Ter (c.541_542delinsTA)?

LDLR p.Pro181Ter (c.541_542delinsTA) is associated with familial hypercholesterolemia (ClinVar).

LDLR p.Pro181Ter

c.541_542delinsTA · VCV3724389

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 4 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.6	GERP 2.4, phastCons 1

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

Variant & gene context

Gene: LDLR
Protein: p.Pro181Ter
Coding: c.541_542delinsTA
MANE Select: NM_000527
Type: Indel
Location: chr19:11105447 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 181: the 'binding to getah virus e1-e2 spike glycoproteins' region; an α-helix; the ldl-receptor class a 4 domain

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

Disease context

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

Similar variants

LDLR p.Pro181Arg Likely pathogenic ★★★ ⚠ same residue
LDLR p.Pro181Leu Pathogenic/Likely pathogenic ★★ ⚠ same residue
LDLR p.Pro181= Conflicting classifications of pathogenicity ★ same residue
LDLR c.1359-31_1359-23delinsCGGCT Uncertain significance ★★★ same condition
LDLR p.Arg744Gln Uncertain significance ★★★ same condition
LDLR p.Val653Ala Uncertain significance ★★★ same condition
LDLR c.313_313+1delinsTC Likely pathogenic ★★ same condition
LDLR p.Cys109Arg 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-pro181ter (accessed [today's date]).

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