Is LDLR p.Pro685Leu (c.2054C>T) pathogenic?

LDLR p.Pro685Leu (c.2054C>T) is classified Pathogenic/Likely pathogenic in LDLR (ClinVar, Multiple submitters, 41 submitters; last evaluated 2026-07-20). AlphaMissense: likely pathogenic (0.8133); Very rare (popmax 0.00668%, eas); Associated with LDLR-related disorder.

What condition is associated with LDLR p.Pro685Leu (c.2054C>T)?

LDLR p.Pro685Leu (c.2054C>T) is associated with LDLR-related disorder, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Pro685Leu (c.2054C>T) in the general population?

LDLR p.Pro685Leu (c.2054C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about LDLR p.Pro685Leu (c.2054C>T)?

AlphaMissense predicts likely pathogenic (score 0.8133) — an in-silico prediction, not a clinical call.

LDLR p.Pro685Leu

c.2054C>T · rs28942084 · VCV3702

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 41 submitters

AlphaMissense

likely pathogenic

0.8133 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

LDLR-related disorder

Computational evidence

Protein change
AlphaMissense	0.8133	likely pathogenic ✓ concordant with ClinVar
REVEL	0.883	moderately pathogenic-leaning
SaProt	LLR -11.62	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	26.7	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

Grpmax group 0.00668% East Asian · 3/44,896 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.00347% 56/1,614,026 alleles · very rare exomes 50/1,461,812 · genomes 6/152,214 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,965
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-American	0.004%	24,979
European (non-Finnish)	0.00398%	25,107

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.Pro685Leu
Coding: c.2054C>T
MANE Select: NM_000527
dbSNP: rs28942084
Type: single nucleotide variant
Location: chr19:11120436 (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

LDLR-related disorder

Also linked: familial hypercholesterolemia hypercholesterolemia, familial, 1 homozygous familial hypercholesterolemia

Similar variants

LDLR p.Pro685Arg Likely pathogenic ★★ same residue
LDLR p.Pro685Gln 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.Pro685= Conflicting classifications of pathogenicity ★ 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-pro685leu (accessed [today's date]).

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