Is LDLR p.Arg574Pro (c.1721G>C) pathogenic?

LDLR p.Arg574Pro (c.1721G>C) is classified Uncertain significance in LDLR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-27). AlphaMissense: likely pathogenic (0.9916); Absent from gnomAD v4.1.

How common is LDLR p.Arg574Pro (c.1721G>C) in the general population?

LDLR p.Arg574Pro (c.1721G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDLR p.Arg574Pro (c.1721G>C)?

AlphaMissense predicts likely pathogenic (score 0.9916) — an in-silico prediction, not a clinical call.

LDLR p.Arg574Pro

c.1721G>C · rs777188764 · VCV2501086

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9916 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9916	likely pathogenic · top 5% in LDLR
REVEL	0.967	strongly pathogenic-leaning
SaProt	LLR -18.27	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 12	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: LDLR
Protein: p.Arg574Pro
Coding: c.1721G>C
MANE Select: NM_000527
dbSNP: rs777188764
Type: single nucleotide variant
Location: chr19:11116874 (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

Similar variants

LDLR p.Arg574His Likely pathogenic ★★★ ⚠ same residue
LDLR p.Arg574Cys Uncertain significance ★★★ ⚠ same residue
LDLR p.Arg574Leu Uncertain significance ★★★ ⚠ same residue
LDLR p.Arg574= Likely benign ★ same residue
LDLR c.1186+5G>A Likely pathogenic ★★★ same type
LDLR c.1359-1G>A Pathogenic ★★★ same type
LDLR c.1359-5C>G Likely pathogenic ★★★ same type
LDLR c.1705+2T>C Likely pathogenic ★★★ same type

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-arg574pro (accessed [today's date]).

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