Is LDLR p.Arg709del (c.2124GAG[1]) pathogenic?

LDLR p.Arg709del (c.2124GAG[1]) is classified Uncertain significance in LDLR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-23). Ultra-rare (popmax 0.0165%, mid); Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Arg709del (c.2124GAG[1])?

LDLR p.Arg709del (c.2124GAG[1]) is associated with familial hypercholesterolemia (ClinVar).

How common is LDLR p.Arg709del (c.2124GAG[1]) in the general population?

LDLR p.Arg709del (c.2124GAG[1]) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

LDLR p.Arg709del

c.2124GAG[1] · rs2077535269 · VCV923754

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1	GERP 1.2, phastCons 1

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,613,544 alleles · ultra-rare exomes 4/1,461,270 · genomes 0/152,274 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000169%	590,012

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.Arg709del
Coding: c.2124GAG[1]
MANE Select: NM_000527
dbSNP: rs2077535269
Type: Microsatellite
Location: chr19:11120506 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 709: the egf-like 3 domain; a β-strand

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.Arg709Gly Uncertain significance ★★★ ⚠ same residue
LDLR p.Arg709_Ser710delinsSerCys Uncertain significance ★ same residue
LDLR p.Arg709= Likely benign ★ same residue
LDLR p.Gly219del Pathogenic ★★★ same condition
LDLR p.Phe403del Likely pathogenic ★★★ same condition
LDLR p.Arg709Lys Uncertain significance ★★★ ⚠ same residue
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-arg709del (accessed [today's date]).

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