Is LDLR p.Pro526Ser (c.1576C>T) pathogenic?

LDLR p.Pro526Ser (c.1576C>T) is classified Uncertain significance in LDLR (ClinVar, Expert panel, 18 submitters; last evaluated 2021-06-09). AlphaMissense: likely pathogenic (0.8696); Very rare (popmax 0.000424%, nfe); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Pro526Ser (c.1576C>T)?

LDLR p.Pro526Ser (c.1576C>T) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia, homozygous familial hypercholesterolemia (ClinVar).

How common is LDLR p.Pro526Ser (c.1576C>T) in the general population?

LDLR p.Pro526Ser (c.1576C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about LDLR p.Pro526Ser (c.1576C>T)?

AlphaMissense predicts likely pathogenic (score 0.8696) — an in-silico prediction, not a clinical call.

LDLR p.Pro526Ser

c.1576C>T · rs730882106 · VCV183120

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 18 submitters

AlphaMissense

likely pathogenic

0.8696 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):

PM2 PS4_Supporting PP3 PP4

Curation rationale (ClinGen, verbatim)

NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4 and PS4_Supportive) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00002326 (0.002%) in European-non Finnish exomes (gnomAD v2.1.1). PP3 - REVEL: 0,952. PP4 - Variant meets PM2. Variant identified in 5 index cases (1 case from Color laboratory with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria; 1 cases from University of British Columbia with DLCN criteria; 2 cases fulfilling Simeon-Broome criteria published in PMID: 9259195). PS4_supporting - Variant meets PM2. Variant identified in 5 index cases.

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

Computational evidence

Protein change
AlphaMissense	0.8696	likely pathogenic
REVEL	0.952	strongly pathogenic-leaning
SaProt	LLR -11.58	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,122 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,612,934 alleles · very rare exomes 4/1,460,852 · genomes 1/152,082 · 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.Pro526Ser
Coding: c.1576C>T
MANE Select: NM_000527
dbSNP: rs730882106
Type: single nucleotide variant
Location: chr19:11113752 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 526: a UniProt-annotated variant site (in fhcl1; uncertain significance; cincinnati-3); a turn

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 homozygous familial hypercholesterolemia

Similar variants

LDLR p.Pro526Arg Uncertain significance ★★★ ⚠ same residue
LDLR p.Pro526His Uncertain significance ★★★ ⚠ same residue
LDLR p.Pro526Leu Uncertain significance ★★★ ⚠ same residue
LDLR p.Pro526Thr 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

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-pro526ser (accessed [today's date]).

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