Is LDLR p.Asp601His (c.1801G>C) pathogenic?

LDLR p.Asp601His (c.1801G>C) is classified Conflicting classifications of pathogenicity in LDLR (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-04-25). AlphaMissense: ambiguous (0.4685); Very rare (popmax 0.00167%, amr); Associated with Cardiovascular phenotype.

What condition is associated with LDLR p.Asp601His (c.1801G>C)?

LDLR p.Asp601His (c.1801G>C) is associated with Cardiovascular phenotype, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Asp601His (c.1801G>C) in the general population?

LDLR p.Asp601His (c.1801G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about LDLR p.Asp601His (c.1801G>C)?

AlphaMissense predicts ambiguous (score 0.4685) — an in-silico prediction, not a clinical call.

LDLR p.Asp601His

c.1801G>C · rs753707206 · VCV252038

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.4685 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4685	ambiguous
REVEL	0.605	indeterminate
SaProt	LLR -11.81	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.47 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.3	GERP 1.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	23.0	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 0.00167% Admixed American · 1/59,980 alleles

Overall 6.84e-05% 1/1,461,876 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.Asp601His
Coding: c.1801G>C
MANE Select: NM_000527
dbSNP: rs753707206
Type: single nucleotide variant
Location: chr19:11116954 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 601: a UniProt-annotated variant site (in fhcl1; uncertain significance)

Full LDLR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypercholesterolemia hypercholesterolemia, familial, 1

Similar variants

LDLR p.Asp601Val Likely pathogenic ★★ same residue
LDLR p.Asp601Asn Uncertain significance ★★ ⚠ same residue
LDLR p.Asp601Tyr Likely pathogenic ★ same residue
LDLR p.Asp601Gly Uncertain significance ★ ⚠ same residue
LDLR p.Asp601= Likely benign ★ same residue
LDLR p.Asp601fs Pathogenic ★ same residue
LDLR c.1186+5G>A Likely pathogenic ★★★ same condition
LDLR c.1359-1G>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-asp601his (accessed [today's date]).

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