Is LDLR p.Asp445Glu (c.1335C>A) pathogenic?

LDLR p.Asp445Glu (c.1335C>A) is classified Conflicting classifications of pathogenicity in LDLR (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-04-01). AlphaMissense: likely pathogenic (0.8957); Very rare (popmax 0.000339%, nfe); Associated with LDLR-related disorder.

What condition is associated with LDLR p.Asp445Glu (c.1335C>A)?

LDLR p.Asp445Glu (c.1335C>A) is associated with LDLR-related disorder, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Asp445Glu (c.1335C>A) in the general population?

LDLR p.Asp445Glu (c.1335C>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about LDLR p.Asp445Glu (c.1335C>A)?

AlphaMissense predicts likely pathogenic (score 0.8957) — an in-silico prediction, not a clinical call.

LDLR p.Asp445Glu

c.1335C>A · rs749780672 · VCV251794

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8957 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

LDLR-related disorder

Computational evidence

Protein change
AlphaMissense	0.8957	likely pathogenic
REVEL	0.924	moderately pathogenic-leaning
SaProt	LLR -9.20	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.14	GERP -3.7, phastCons 0.064
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	21.6	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) · 4/1,180,042 alleles

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

Overall 0.00118% 19/1,613,858 alleles · very rare exomes 18/1,461,698 · genomes 1/152,160 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0172%	5,804
Remaining individualsnot grpmax-eligible	0.0064%	15,621
European (non-Finnish)grpmax	0.000339%	295,010

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp445Glu
Coding: c.1335C>A
MANE Select: NM_000527
dbSNP: rs749780672
Type: single nucleotide variant
Location: chr19:11113426 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 445: a β-strand

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

Disease context

LDLR-related disorder

Also linked: familial hypercholesterolemia hypercholesterolemia, familial, 1

Similar variants

LDLR p.Asp445= Likely benign ★★ same residue
LDLR p.Asp445Tyr Conflicting classifications of pathogenicity ★ ⚠ 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-asp445glu (accessed [today's date]).

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