Is LDLR p.Asp525Val (c.1574A>T) pathogenic?

LDLR p.Asp525Val (c.1574A>T) is classified Likely pathogenic in LDLR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). AlphaMissense: likely pathogenic (0.9457); Very rare (popmax 8.48e-05%, nfe); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Asp525Val (c.1574A>T)?

LDLR p.Asp525Val (c.1574A>T) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Asp525Val (c.1574A>T) in the general population?

LDLR p.Asp525Val (c.1574A>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about LDLR p.Asp525Val (c.1574A>T)?

AlphaMissense predicts likely pathogenic (score 0.9457) — an in-silico prediction, not a clinical call.

LDLR p.Asp525Val

c.1574A>T · rs879254943 · VCV251902

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9457 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypercholesterolemia, familial, 1

Computational evidence

Protein change
AlphaMissense	0.9457	likely pathogenic ✓ concordant with ClinVar
REVEL	0.963	strongly pathogenic-leaning
SaProt	LLR -14.30	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.51 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	29.7	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 8.48e-05% European (non-Finnish) · 1/1,179,266 alleles

Overall 6.2e-05% 1/1,613,262 alleles · very rare exomes 1/1,461,008 · genomes 0/152,254 · 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.Asp525Val
Coding: c.1574A>T
MANE Select: NM_000527
dbSNP: rs879254943
Type: single nucleotide variant
Location: chr19:11113750 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 525: 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.Asp525Ala Uncertain significance ★ ⚠ same residue
LDLR p.Asp525Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
LDLR p.Asp525Gly Uncertain significance ★ ⚠ same residue
LDLR p.Asp525His Uncertain significance ★ ⚠ same residue
LDLR p.Asp525= Likely benign ★ 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

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-asp525val (accessed [today's date]).

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