Is LDLR p.Ile623fs (c.1867_1868del) pathogenic?

LDLR p.Ile623fs (c.18671868del) is classified Pathogenic in LDLR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2023-12-14). Very rare (popmax 8.47e-05%, nfe); Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Ile623fs (c.1867_1868del)?

LDLR p.Ile623fs (c.1867_1868del) is associated with familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Ile623fs (c.1867_1868del) in the general population?

LDLR p.Ile623fs (c.1867_1868del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

LDLR p.Ile623fs

c.1867_1868del · rs879255061 · VCV252095

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

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 13 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,028 alleles

Overall 6.84e-05% 1/1,461,870 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.Ile623fs
Coding: c.1867_1868del
MANE Select: NM_000527
dbSNP: rs879255061
Type: Microsatellite
Location: chr19:11120111 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 623: a turn

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

Also linked: hypercholesterolemia, familial, 1

Similar variants

LDLR p.Ile623Thr Uncertain significance ★★★ ⚠ same residue
LDLR p.Ile623Val Uncertain significance ★★★ ⚠ same residue
LDLR p.Ile623= Likely benign ★★ same residue
LDLR p.Ile623Phe Uncertain significance ★ ⚠ same residue
LDLR p.Gly219del Pathogenic ★★★ same condition
LDLR p.Phe403del Likely pathogenic ★★★ same condition
LDLR c.190+2_190+3del Likely pathogenic ★★ same condition
LDLR p.Arg124fs 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-ile623fs (accessed [today's date]).

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