Is LDLR p.Pro181Leu (c.542C>T) pathogenic?

LDLR p.Pro181Leu (c.542C>T) is classified Pathogenic/Likely pathogenic in LDLR (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-06-04). AlphaMissense: likely benign (0.1377); Very rare (popmax 0.0011%, sas); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Pro181Leu (c.542C>T)?

LDLR p.Pro181Leu (c.542C>T) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Pro181Leu (c.542C>T) in the general population?

LDLR p.Pro181Leu (c.542C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about LDLR p.Pro181Leu (c.542C>T)?

AlphaMissense predicts likely benign (score 0.1377) — an in-silico prediction, not a clinical call.

LDLR p.Pro181Leu

c.542C>T · rs557344672 · VCV431512

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1377 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypercholesterolemia, familial, 1

Computational evidence

Protein change
AlphaMissense	0.1377	likely benign ⚠ discordant with ClinVar
REVEL	0.83	moderately pathogenic-leaning
SaProt	LLR -6.05	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	22.7	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 0.0011% South Asian · 1/91,092 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000805% 13/1,613,924 alleles · very rare exomes 12/1,461,720 · genomes 1/152,204 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,092
European (non-Finnish)	0.00102%	98,337

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.Pro181Leu
Coding: c.542C>T
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.Pro181Arg 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-pro181leu (accessed [today's date]).

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