Is LDLR p.Ala684Pro (c.2050G>C) pathogenic?

LDLR p.Ala684Pro (c.2050G>C) is classified Uncertain significance in LDLR (ClinVar, Expert panel, 1 submitter; last evaluated 2025-02-20). AlphaMissense: likely pathogenic (0.7427); Absent from gnomAD v4.1; Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Ala684Pro (c.2050G>C)?

LDLR p.Ala684Pro (c.2050G>C) is associated with hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Ala684Pro (c.2050G>C) in the general population?

LDLR p.Ala684Pro (c.2050G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDLR p.Ala684Pro (c.2050G>C)?

AlphaMissense predicts likely pathogenic (score 0.7427) — an in-silico prediction, not a clinical call.

LDLR p.Ala684Pro

c.2050G>C · VCV4073624

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7427 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypercholesterolemia, familial, 1

Computational evidence

Protein change
AlphaMissense	0.7427	likely pathogenic
REVEL	0.817	moderately pathogenic-leaning
SaProt	LLR -15.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.24	acceptor gain · deltas
Pangolin	Δ0.22	gain · loss 0.00 · agrees with SpliceAI · independent
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	31.0	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.Ala684Pro
Coding: c.2050G>C
MANE Select: NM_000527
Type: single nucleotide variant
Location: chr19:11120432 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 684: the egf-like 3 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

Similar variants

LDLR p.Ala684Thr Uncertain significance ★★★ ⚠ same residue
LDLR p.Ala684Val Uncertain significance ★★★ ⚠ same residue
LDLR p.Ala684= Likely benign ★★ same residue
LDLR p.Ala684fs 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

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-ala684pro (accessed [today's date]).

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