Is LDLR p.Pro685= (c.2055G>A) pathogenic?

LDLR p.Pro685= (c.2055G>A) is classified Conflicting classifications of pathogenicity in LDLR (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-10-29). Ultra-rare (popmax 0.0893%, afr); Associated with Cardiovascular phenotype.

What condition is associated with LDLR p.Pro685= (c.2055G>A)?

LDLR p.Pro685= (c.2055G>A) is associated with Cardiovascular phenotype, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Pro685= (c.2055G>A) in the general population?

LDLR p.Pro685= (c.2055G>A) is ultra-rare (popmax 0.0893%, afr) (gnomAD).

LDLR p.Pro685=

c.2055G>A · rs149126953 · VCV526762

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0893%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.1	GERP -5.1
Overall
CADD	0.217	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0893% African / African-American · 67/75,054 alleles

Filtering AF 0.0721% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0658%

Overall 0.00874% 141/1,614,038 alleles · ultra-rare exomes 84/1,461,770 · genomes 57/152,268 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0893%	1,120
Admixed American	0.00667%	14,998
European (non-Finnish)	0.00542%	18,438
Remaining individualsnot grpmax-eligible	0.0048%	20,835
East Asian	0.00223%	44,880
South Asian	0.0022%	45,541

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.Pro685=
Coding: c.2055G>A
MANE Select: NM_000527
dbSNP: rs149126953
Type: single nucleotide variant
Location: chr19:11120437 (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

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

Also linked: familial hypercholesterolemia hypercholesterolemia, familial, 1

Similar variants

LDLR p.Pro685Arg Likely pathogenic ★★ same residue
LDLR p.Pro685Gln Likely pathogenic ★★ same residue
LDLR p.Pro685Leu Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Pro685Ser Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Pro685Ala Likely pathogenic ★ ⚠ same residue
LDLR p.Pro685Thr Likely pathogenic ★ same residue
LDLR p.Pro685fs Pathogenic ★★ same residue
LDLR c.1186+5G>A 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-pro685 (accessed [today's date]).

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