Is LDLR p.Pro699Leu (c.2096C>T) pathogenic?

LDLR p.Pro699Leu (c.2096C>T) is classified Uncertain significance in LDLR (ClinVar, Expert panel, 31 submitters; last evaluated 2021-06-18). AlphaMissense: likely pathogenic (0.7062); Ultra-rare (popmax 0.0294%, afr); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Pro699Leu (c.2096C>T)?

LDLR p.Pro699Leu (c.2096C>T) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia, homozygous familial hypercholesterolemia (ClinVar).

How common is LDLR p.Pro699Leu (c.2096C>T) in the general population?

LDLR p.Pro699Leu (c.2096C>T) is ultra-rare (popmax 0.0294%, afr) (gnomAD).

What do computational predictors say about LDLR p.Pro699Leu (c.2096C>T)?

AlphaMissense predicts likely pathogenic (score 0.7062) — an in-silico prediction, not a clinical call.

LDLR p.Pro699Leu

c.2096C>T · rs201573863 · VCV252219

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 31 submitters

AlphaMissense

likely pathogenic

0.7062 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0294%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):

PP1_Strong PP3 BS4

Curation rationale (ClinGen, verbatim)

NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu) variant is classified as Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (BS4, PP1_Strong and PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BS4 - Variant does not segregate with FH phenotype in 11 informative meioses in 6 families (Laboratory of Genetics and Molecular Cardiology). PP1_strong - Variant segregates with FH phenotype in 58 informative meioses in 9 families from Laboratory of Genetics and Molecular Cardiology. PP3 - REVEL: 0,92.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.7062	likely pathogenic
REVEL	0.92	moderately pathogenic-leaning
SaProt	LLR -11.60	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 7.6	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

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

Grpmax group 0.0294% African / African-American · 22/74,906 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00211% 34/1,613,706 alleles · ultra-rare exomes 20/1,461,566 · genomes 14/152,140 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0294%	3,405
South Asian	0.00439%	22,772
Admixed American	0.00167%	59,976
European (non-Finnish)	0.000593%	168,576

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.Pro699Leu
Coding: c.2096C>T
MANE Select: NM_000527
dbSNP: rs201573863
Type: single nucleotide variant
Location: chr19:11120478 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 699: the egf-like 3 domain; a UniProt-annotated variant site (in fhcl1; uncertain significance)

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

Also linked: familial hypercholesterolemia homozygous familial hypercholesterolemia

Similar variants

LDLR p.Pro699= Likely benign ★★ same residue
LDLR p.Pro699Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
LDLR p.Pro699fs 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
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-pro699leu (accessed [today's date]).

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