Is LDLR p.Ile588= (c.1764C>T) pathogenic?

LDLR p.Ile588= (c.1764C>T) is classified Benign/Likely benign in LDLR (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-04-26). Ultra-rare (popmax 0.0958%, eas); Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Ile588= (c.1764C>T)?

LDLR p.Ile588= (c.1764C>T) is associated with familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Ile588= (c.1764C>T) in the general population?

LDLR p.Ile588= (c.1764C>T) is ultra-rare (popmax 0.0958%, eas) (gnomAD).

LDLR p.Ile588=

c.1764C>T · rs778595540 · VCV704178

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0958%, eas)

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP -15	GERP -3.7
Overall
CADD	0.182	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0958% East Asian · 43/44,888 alleles

Filtering AF 0.0731% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.065%

Overall 0.00297% 48/1,613,850 alleles · ultra-rare exomes 47/1,461,762 · genomes 1/152,088 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0958%	1,044
Remaining individualsnot grpmax-eligible	0.0016%	62,474
European (non-Finnish)	0.000339%	294,981

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.Ile588=
Coding: c.1764C>T
MANE Select: NM_000527
dbSNP: rs778595540
Type: single nucleotide variant
Location: chr19:11116917 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 588: a β-strand

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

Also linked: hypercholesterolemia, familial, 1

Similar variants

LDLR p.Ile588Met Uncertain significance ★★ ⚠ 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
LDLR c.2140+1G>A Pathogenic ★★★ same condition
LDLR c.2389+2T>G 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-ile588 (accessed [today's date]).

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