Is LDLR p.Pro685Ala (c.2053C>G) pathogenic?

LDLR p.Pro685Ala (c.2053C>G) is classified Likely pathogenic in LDLR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-02). AlphaMissense: ambiguous (0.4731); Absent from gnomAD v4.1; Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Pro685Ala (c.2053C>G)?

LDLR p.Pro685Ala (c.2053C>G) is associated with familial hypercholesterolemia (ClinVar).

How common is LDLR p.Pro685Ala (c.2053C>G) in the general population?

LDLR p.Pro685Ala (c.2053C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDLR p.Pro685Ala (c.2053C>G)?

AlphaMissense predicts ambiguous (score 0.4731) — an in-silico prediction, not a clinical call.

LDLR p.Pro685Ala

c.2053C>G · VCV3636911

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4731 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
AlphaMissense	0.4731	ambiguous
REVEL	0.81	moderately pathogenic-leaning
SaProt	LLR -9.49	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.21	acceptor loss · deltas
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	24.4	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.Pro685Ala
Coding: c.2053C>G
MANE Select: NM_000527
Type: single nucleotide variant
Location: chr19:11120435 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 685: the egf-like 3 domain; a UniProt-annotated variant site (in fhcl1; gujerat/zambia/belgian/dutch/sweden/japan)

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

Disease context

familial hypercholesterolemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LDLR p.Pro685Arg Likely pathogenic ★★ same residue
LDLR p.Pro685Leu Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Pro685= Conflicting classifications of pathogenicity ★ same residue
LDLR p.Pro685Gln Likely pathogenic ★★ same residue
LDLR p.Pro685Ser Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Pro685Thr Likely pathogenic ★ same residue
LDLR c.1186+5G>A Likely pathogenic ★★★ same condition
LDLR c.1359-1G>A 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-pro685ala (accessed [today's date]).

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