Is LDLR p.Arg300= (c.900A>G) pathogenic?

LDLR p.Arg300= (c.900A>G) is classified Likely benign in LDLR (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-04). Very rare (popmax 0.00017%, nfe); Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Arg300= (c.900A>G)?

LDLR p.Arg300= (c.900A>G) is associated with familial hypercholesterolemia (ClinVar).

How common is LDLR p.Arg300= (c.900A>G) in the general population?

LDLR p.Arg300= (c.900A>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

LDLR p.Arg300=

c.900A>G · rs2515977878 · VCV2186961

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.6	GERP -1.9, phastCons 1
Overall
CADD	5.951	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,177,606 alleles

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

Overall 0.000124% 2/1,610,212 alleles · very rare exomes 2/1,458,314 · genomes 0/151,898 · 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.Arg300=
Coding: c.900A>G
MANE Select: NM_000527
dbSNP: rs2515977878
Type: single nucleotide variant
Location: chr19:11107474 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 300: the ldl-receptor class a 7 domain; a UniProt-annotated variant site (in fhcl1; likely pathogenic; does not affect receptor expression at the cell surface; results in reduced ldl binding; results in reduced ldl uptake and internalization)

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.Arg300Gly Likely pathogenic ★★★ same residue
LDLR p.Arg300Lys Uncertain significance ★★★ ⚠ same residue
LDLR p.Arg300Thr Uncertain significance ★★ ⚠ same residue
LDLR p.Arg300Ter Pathogenic ★ 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.190+4A>T 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-arg300 (accessed [today's date]).

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