Is LDLR p.Pro181Arg (c.542C>G) pathogenic?

LDLR p.Pro181Arg (c.542C>G) is classified Likely pathogenic in LDLR (ClinVar, Expert panel, 25 submitters; last evaluated 2024-02-23). AlphaMissense: likely benign (0.1714); Very rare (popmax 0.00161%, nfe); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Pro181Arg (c.542C>G)?

LDLR p.Pro181Arg (c.542C>G) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Pro181Arg (c.542C>G) in the general population?

LDLR p.Pro181Arg (c.542C>G) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about LDLR p.Pro181Arg (c.542C>G)?

AlphaMissense predicts likely benign (score 0.1714) — an in-silico prediction, not a clinical call.

LDLR p.Pro181Arg

c.542C>G · rs557344672 · VCV183089

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 25 submitters

AlphaMissense

likely benign

0.1714 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

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

PM2 PS3_Moderate PS4_Moderate PM1 PP4

Curation rationale (ClinGen, verbatim)

The NM_000527.5(LDLR):c.542C>G (p.Pro181Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PS3_Moderate, PS4_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.00005 (0.005%) in European (Non-Finnish) exomes+genomes (gnomAD v4.0.0). PM1: Variant meets PM2 and is a missense in exon 4. PS3_Moderate: Level 2 assay: PMID 21868016 (Garcia-Garcia A et al., 2011): COS-7 cells. Mature/precursor LDLR forms ratio ~60% ---- Overall LDLR biosynthesis is below 70% of wild-type activity. PS4_Moderate, PP4: Variant meets PM2 and is identified in at least 6 unrelated index cases who fulfill criteria for FH (1 case from PMID 16250003 (Fouchier SW et al., 2005); 2 cases with MedPed and Simon Broome criteria from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic, and PMID 22698793 (Tichý L et al., 2012); 2 cases meeting Simon Broome and DLCN criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 1 case with DLCN score>=6 from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia).

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

Computational evidence

Protein change
AlphaMissense	0.1714	likely benign ⚠ discordant with ClinVar
REVEL	0.713	pathogenic-leaning
SaProt	LLR -5.78	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -0.84, phastCons 0.67
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	22.3	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 0.00161% European (non-Finnish) · 19/1,180,042 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00124% 20/1,613,924 alleles · very rare exomes 19/1,461,720 · genomes 1/152,204 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00161%	62,108
African / African-American	0.00133%	74,932

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.Pro181Arg
Coding: c.542C>G
MANE Select: NM_000527
dbSNP: rs557344672
Type: single nucleotide variant
Location: chr19:11105448 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 181: the 'binding to getah virus e1-e2 spike glycoproteins' region; an α-helix; the ldl-receptor class a 4 domain

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.Pro181Leu Pathogenic/Likely pathogenic ★★ ⚠ same residue
LDLR p.Pro181= Conflicting classifications of pathogenicity ★ same residue
LDLR p.Pro181Ter 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
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-pro181arg (accessed [today's date]).

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