Is LDLR p.Asp482His (c.1444G>C) pathogenic?

LDLR p.Asp482His (c.1444G>C) is classified Likely pathogenic in LDLR (ClinVar, Expert panel, 3 submitters; last evaluated 2023-06-23). AlphaMissense: likely pathogenic (0.9957); Very rare (popmax 8.47e-05%, nfe); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Asp482His (c.1444G>C)?

LDLR p.Asp482His (c.1444G>C) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Asp482His (c.1444G>C) in the general population?

LDLR p.Asp482His (c.1444G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about LDLR p.Asp482His (c.1444G>C)?

AlphaMissense predicts likely pathogenic (score 0.9957) — an in-silico prediction, not a clinical call.

LDLR p.Asp482His

c.1444G>C · rs139624145 · VCV251844

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9957 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

Likely Pathogenic for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):

PM2 PS4_Supporting PS3_Moderate PP3 PP4 PM5

Curation rationale (ClinGen, verbatim)

The NM_000527.5(LDLR):c.1444G>C (p.Asp482His) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3_Moderate, PM2, PM5, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL=0.993. PM5: 3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1444G>A (p.Asp482Asn) (ClinVar ID 161284) - Pathogenic by these guidelines; - NM_000527.5(LDLR):c.1444G>T (p.Asp482Tyr) (ClinVar ID 251845) - Uncertain significance by these guidelines; - NM_000527.5(LDLR):c.1445A>G (p.Asp482Gly) (ClinVar ID 251846) - Likely Pathogenic by these guidelines; There is 1 variant in the same codon classified as Pathogenic by these guidelines. PS3_Moderate: Level 2 assay: PMID 31587492 (Kizhakkedath P et al., 2019) - HEK-293T cells. In immunoblots of the mutants, only the precursor form was observed (~120 kDa) and the mature receptor form was absent. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 2 index cases who fulfill Simon Broome criteria for FH (1 case in PMID 11313767 (Heath KE et al., 2001), 1 case in PMID 10559517 (Graham CA et al., 1999)).

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

Computational evidence

Protein change
AlphaMissense	0.9957	likely pathogenic ✓ concordant with ClinVar · top 3% in LDLR
REVEL	0.993	strongly pathogenic-leaning
SaProt	LLR -14.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	32.0	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 8.47e-05% European (non-Finnish) · 1/1,179,972 alleles

Overall 6.84e-05% 1/1,461,744 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.Asp482His
Coding: c.1444G>C
MANE Select: NM_000527
dbSNP: rs139624145
Type: single nucleotide variant
Location: chr19:11113620 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 482: a UniProt-annotated variant site (in fhcl1); 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.Asp482Asn Pathogenic ★★★ same residue
LDLR p.Asp482Gly Likely pathogenic ★★★ same residue
LDLR p.Asp482Tyr Uncertain significance ★★★ ⚠ 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

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-asp482his (accessed [today's date]).

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