Is LDLR p.Ile796= (c.2388C>T) pathogenic?

LDLR p.Ile796= (c.2388C>T) is classified Uncertain significance in LDLR (ClinVar, Expert panel, 9 submitters; last evaluated 2025-03-28). Very rare (popmax 0.00424%, nfe); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Ile796= (c.2388C>T)?

LDLR p.Ile796= (c.2388C>T) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Ile796= (c.2388C>T) in the general population?

LDLR p.Ile796= (c.2388C>T) is very rare (popmax 0.00424%, nfe) (gnomAD).

LDLR p.Ile796=

c.2388C>T · rs543852919 · VCV406165

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00424%, nfe)

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

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

PM2

Curation rationale (ClinGen, verbatim)

The NM_000527.5(LDLR): c.2388C>T (p.Ile796=) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025. The supporting evidence is as follows: PM2: PopMax MAF= 0.00004238 (0.004238%) in European non-Finnish exomes + genomes (gnomAD v.4.1.0).

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

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 -9.7	GERP -2.8
Overall
CADD	0.057	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00424% European (non-Finnish) · 50/1,179,798 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00294%

Overall 0.00347% 56/1,613,844 alleles · very rare exomes 52/1,461,590 · genomes 4/152,254 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00424%	23,596
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Remaining individualsnot grpmax-eligible	0.0032%	31,250
East Asian	0.00223%	44,864
Admixed American	0.00167%	60,002
African / African-American	0.00133%	75,034

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.Ile796=
Coding: c.2388C>T
MANE Select: NM_000527
dbSNP: rs543852919
Type: single nucleotide variant
Location: chr19:11128084 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB

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

Similar variants

LDLR p.Ile796Val Uncertain significance ★★ ⚠ same residue
LDLR p.Ile796Ser Uncertain significance ★ ⚠ same residue
LDLR p.Ile796fs Pathogenic/Likely 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-ile796 (accessed [today's date]).

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