Is LDLR p.Arg574Cys (c.1720C>T) pathogenic?

LDLR p.Arg574Cys (c.1720C>T) is classified Uncertain significance in LDLR (ClinVar, Expert panel, 19 submitters; last evaluated 2022-03-07). AlphaMissense: ambiguous (0.5532); Ultra-rare (popmax 0.0338%, mid); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Arg574Cys (c.1720C>T)?

LDLR p.Arg574Cys (c.1720C>T) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Arg574Cys (c.1720C>T) in the general population?

LDLR p.Arg574Cys (c.1720C>T) is ultra-rare (popmax 0.0338%, mid) (gnomAD).

What do computational predictors say about LDLR p.Arg574Cys (c.1720C>T)?

AlphaMissense predicts ambiguous (score 0.5532) — an in-silico prediction, not a clinical call.

LDLR p.Arg574Cys

c.1720C>T · rs185098634 · VCV183123

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 19 submitters

AlphaMissense

ambiguous

0.5532 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0338%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

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

PM2 PS4_Supporting PP3 PP4 BS3_Supporting

Curation rationale (ClinGen, verbatim)

NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_supporting and BS3_supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001384 (0.01384%) in Other populations exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.967. PP4 - Variant meets PM2. Variant identified in 5 FH cases (1 case with Simon-Broome possible from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case with Dutch Lipid Clinic Network score ≥ 6 published in PMID: 11462246; 1 case with Dutch Lipid Clinic Network score ≥ 6 published in PMID: 29290422; 1 case with Dutch Lipid Clinic Network score ≥ 6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca; 1 case with Simon-Broome register possible/definite published in PMID: 26892515. PS4_supporting - Variant meets PM2. Variant identified in 5 unrelated index cases (1 case with Simon-Broome from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case with Dutch Lipid Clinic Network score ≥ 6 published in PMID: 11462246; 1 case with Dutch Lipid Clinic Network score ≥ 6 published in PMID: 29290422; 1 case with Dutch Lipid Clinic Network score ≥ 6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca; 1 case with Simon-Broome register criteria published in PMID: 26892515. BS3_supporting - PMID: 25647241: Level 3 assay - study on HeLa-Kyoto cells, LDLR-GFP construct, WB + CLSM assays, whole cycle is above 100% of wild-type activity. - functional study is consistent with no damaging effect.

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

Computational evidence

Protein change
AlphaMissense	0.5532	ambiguous
REVEL	0.967	strongly pathogenic-leaning
SaProt	LLR -14.88	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	32.0	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 0.0338% Middle Eastern · 2/5,916 alleles

Filtering AF 0.00595% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00247%

Overall 0.00161% 26/1,613,906 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0338%	2,958
Remaining individualsnot grpmax-eligible	0.0048%	20,830
Admixed American	0.00167%	59,992
Finnishnot grpmax-eligible	0.00156%	64,018
European (non-Finnish)	0.00153%	65,555
South Asian	0.0011%	91,066

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.Arg574Cys
Coding: c.1720C>T
MANE Select: NM_000527
dbSNP: rs185098634
Type: single nucleotide variant
Location: chr19:11116873 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 574: a UniProt-annotated variant site (in fhcl1; uncertain significance); a UniProt-annotated variant site (in fhcl1; likely pathogenic); a β-strand

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.Arg574His Likely pathogenic ★★★ ⚠ same residue
LDLR p.Arg574Leu Uncertain significance ★★★ ⚠ same residue
LDLR p.Arg574= Likely benign ★ same residue
LDLR p.Arg574Pro 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-arg574cys (accessed [today's date]).

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