Is LDLR p.Gln366Pro (c.1097A>C) pathogenic?

LDLR p.Gln366Pro (c.1097A>C) is classified Likely pathogenic in LDLR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-15). AlphaMissense: likely pathogenic (0.878); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with LDLR p.Gln366Pro (c.1097A>C)?

LDLR p.Gln366Pro (c.1097A>C) is associated with Cardiovascular phenotype, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Gln366Pro (c.1097A>C) in the general population?

LDLR p.Gln366Pro (c.1097A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDLR p.Gln366Pro (c.1097A>C)?

AlphaMissense predicts likely pathogenic (score 0.878) — an in-silico prediction, not a clinical call.

LDLR p.Gln366Pro

c.1097A>C · rs746982741 · VCV251661

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.878 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.878	likely pathogenic ✓ concordant with ClinVar
REVEL	0.972	strongly pathogenic-leaning
SaProt	LLR -16.11	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 11	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	28.0	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

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.Gln366Pro
Coding: c.1097A>C
MANE Select: NM_000527
dbSNP: rs746982741
Type: single nucleotide variant
Location: chr19:11111550 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 366: the egf-like 2; calcium-binding domain; a UniProt-annotated variant site (in fhcl1); a β-strand

Full LDLR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypercholesterolemia, familial, 1

Similar variants

LDLR p.Gln366Ter Pathogenic ★★ same residue
LDLR p.Gln366Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
LDLR p.Gln366_Asn370delinsHis Conflicting classifications of pathogenicity ★ 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-gln366pro (accessed [today's date]).

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