Is LDLR p.Asp131fs (c.389dup) pathogenic?

LDLR p.Asp131fs (c.389dup) is classified Pathogenic in LDLR (ClinVar, Single submitter, 2 submitters; last evaluated 2016-03-25). Very rare (popmax 0.00223%, eas); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Asp131fs (c.389dup)?

LDLR p.Asp131fs (c.389dup) is associated with hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Asp131fs (c.389dup) in the general population?

LDLR p.Asp131fs (c.389dup) is very rare (popmax 0.00223%, eas) (gnomAD).

LDLR p.Asp131fs

c.389dup · rs879254510 · VCV251199

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

hypercholesterolemia, familial, 1

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 4 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.3	GERP -4.5

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,888 alleles

Overall 6.2e-05% 1/1,613,784 alleles · very rare exomes 1/1,461,478 · genomes 0/152,306 · joint denominator

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.Asp131fs
Coding: c.389dup
MANE Select: NM_000527
dbSNP: rs879254510
Type: Duplication
Location: chr19:11105294 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 131: a β-strand; the ldl-receptor class a 3 domain

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

Disease context

hypercholesterolemia, familial, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LDLR p.Asp131Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
LDLR p.Asp131His Conflicting classifications of pathogenicity ★ ⚠ same residue
LDLR p.Glu763fs Likely pathogenic ★★★ same condition
LDLR p.Cys803_Leu808dup Uncertain significance ★★★ same condition
LDLR c.313+1dup Pathogenic/Likely pathogenic ★★ same condition
LDLR c.313+2dup Pathogenic/Likely pathogenic ★★ same condition
LDLR c.314-446_1187-386dup Pathogenic/Likely pathogenic ★★ same condition
LDLR p.Ala13fs 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-asp131fs (accessed [today's date]).

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