Is LDLR p.Glu258= (c.774A>G) pathogenic?

LDLR p.Glu258= (c.774A>G) is classified Likely benign in LDLR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-24). Very rare (popmax 0.00333%, amr); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Glu258= (c.774A>G)?

LDLR p.Glu258= (c.774A>G) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Glu258= (c.774A>G) in the general population?

LDLR p.Glu258= (c.774A>G) is very rare (popmax 0.00333%, amr) (gnomAD).

LDLR p.Glu258=

c.774A>G · rs1307291980 · VCV834673

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

hypercholesterolemia, familial, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.77	GERP -3.7
Overall
CADD	4.279	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,008 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000186% 3/1,614,216 alleles · very rare exomes 3/1,461,886 · genomes 0/152,330 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,004
Remaining individualsnot grpmax-eligible	0.0016%	62,512

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.Glu258=
Coding: c.774A>G
MANE Select: NM_000527
dbSNP: rs1307291980
Type: single nucleotide variant
Location: chr19:11106644 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 258: the ldl-receptor class a 6 domain; a β-strand

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

Also linked: familial hypercholesterolemia

Similar variants

LDLR p.Glu258Ter Pathogenic ★★ same residue
LDLR p.Glu258Lys Likely benign ★ same residue
LDLR p.Glu258_Tyr259insTer Pathogenic ★ same residue
LDLR p.Glu258fs Likely 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.1705+2T>C 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-glu258 (accessed [today's date]).

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