Is LDLR p.Ala151Pro (c.451G>C) pathogenic?

LDLR p.Ala151Pro (c.451G>C) is classified Conflicting classifications of pathogenicity in LDLR (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2024-08-26). AlphaMissense: likely benign (0.1356); Very rare (popmax 0.000254%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with LDLR p.Ala151Pro (c.451G>C)?

LDLR p.Ala151Pro (c.451G>C) is associated with Cardiovascular phenotype, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Ala151Pro (c.451G>C) in the general population?

LDLR p.Ala151Pro (c.451G>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about LDLR p.Ala151Pro (c.451G>C)?

AlphaMissense predicts likely benign (score 0.1356) — an in-silico prediction, not a clinical call.

LDLR p.Ala151Pro

c.451G>C · rs763233960 · VCV251234

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1356 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1356	likely benign
REVEL	0.589	indeterminate
SaProt	LLR -8.97	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.91	GERP -5.1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	15.81	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 0.000254% European (non-Finnish) · 3/1,179,970 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,652 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.Ala151Pro
Coding: c.451G>C
MANE Select: NM_000527
dbSNP: rs763233960
Type: single nucleotide variant
Location: chr19:11105357 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 151: the 'binding to getah virus e1-e2 spike glycoproteins' region; a β-strand; a disulfide bond; the ldl-receptor class a 4 domain

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.Ala151= Conflicting classifications of pathogenicity ★ same residue
LDLR p.Ala151Ser Uncertain significance ★ ⚠ same residue
LDLR p.Ala151Thr Likely benign ★ same residue
LDLR p.Ala151del Likely pathogenic ★★ same residue
LDLR p.Ala151fs 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

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-ala151pro (accessed [today's date]).

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