Is LDLR p.Arg709Lys (c.2126G>A) pathogenic?

LDLR p.Arg709Lys (c.2126G>A) is classified Uncertain significance in LDLR (ClinVar, Expert panel, 2 submitters; last evaluated 2024-10-28). AlphaMissense: likely benign (0.113); Very rare (popmax 0.000339%, nfe); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Arg709Lys (c.2126G>A)?

LDLR p.Arg709Lys (c.2126G>A) is associated with hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Arg709Lys (c.2126G>A) in the general population?

LDLR p.Arg709Lys (c.2126G>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about LDLR p.Arg709Lys (c.2126G>A)?

AlphaMissense predicts likely benign (score 0.113) — an in-silico prediction, not a clinical call.

LDLR p.Arg709Lys

c.2126G>A · rs730882113 · VCV183132

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.113 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):

PM2 PP3

Curation rationale (ClinGen, verbatim)

The NM_000527.5 (LDLR):c.2126G>A (p.Arg709Lys) variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024. The supporting evidence is as follows: PM2: PopMax MAF=0.000003390 in non-Finnish European exomes+genomes (gnomAD v4.1.0). PP3: REVEL=0.842.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.113	likely benign
REVEL	0.842	moderately pathogenic-leaning
SaProt	LLR -5.38	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP -1.7, phastCons 0.99
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,020 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,456 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.Arg709Lys
Coding: c.2126G>A
MANE Select: NM_000527
dbSNP: rs730882113
Type: single nucleotide variant
Location: chr19:11120508 (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; a disulfide bond

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.Arg709Gly Uncertain significance ★★★ ⚠ same residue
LDLR p.Arg709= Likely benign ★ same residue
LDLR c.1186+5G>A Likely pathogenic ★★★ same condition
LDLR c.1359-1G>A Pathogenic ★★★ same condition
LDLR c.1359-5C>G Likely pathogenic ★★★ same condition
LDLR c.1705+2T>C Likely pathogenic ★★★ same condition
LDLR c.190+4A>T Likely pathogenic ★★★ same condition
LDLR c.2140+1G>A 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-arg709lys (accessed [today's date]).

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