Is LDLR p.Pro539= (c.1617C>T) pathogenic?

LDLR p.Pro539= (c.1617C>T) is classified Benign/Likely benign in LDLR (ClinVar, Multiple submitters, 21 submitters; last evaluated 2026-02-04). Common (popmax 29.6%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with LDLR p.Pro539= (c.1617C>T)?

LDLR p.Pro539= (c.1617C>T) is associated with Cardiovascular phenotype, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

LDLR p.Pro539=

Q: How common is LDLR p.Pro539= (c.1617C>T) in the general population?

LDLR p.Pro539= (c.1617C>T) is common (popmax 29.6%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1617C>T · rs5929 · VCV251936

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 21 submitters

gnomAD v4.1

Common

common (popmax 29.6%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -5
Overall
CADD	0.19	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 29.6% East Asian · 13,280/44,824 alleles

Filtering AF 29.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 29%

Overall 5.51% 88,787/1,612,458 alleles · common exomes 77,739/1,460,330 · genomes 11,048/152,128 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	29.6%	3
African / African-American	11.3%	9
South Asian	8.04%	12
Admixed American	6.94%	14
Ashkenazi Jewishnot grpmax-eligible	6.35%	16
Remaining individualsnot grpmax-eligible	5.81%	17
Middle Eastern	5.68%	18
Finnishnot grpmax-eligible	5.39%	19
European (non-Finnish)	3.92%	25
Amishnot grpmax-eligible	1.97%	51

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.Pro539=
Coding: c.1617C>T
MANE Select: NM_000527
dbSNP: rs5929
Type: single nucleotide variant
Location: chr19:11116124 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 539: a β-strand

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 Smith-Lemli-Opitz syndrome

Similar variants

LDLR p.Pro539Ser 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
LDLR c.2140+1G>A Pathogenic ★★★ same condition
LDLR c.2389+2T>G 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-pro539 (accessed [today's date]).

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