Is LDLR p.Ile398= (c.1194C>T) pathogenic?

LDLR p.Ile398= (c.1194C>T) is classified Likely benign in LDLR (ClinVar, Expert panel, 18 submitters; last evaluated 2022-08-29). Low-frequency (popmax 1.66%, eas); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Ile398= (c.1194C>T)?

LDLR p.Ile398= (c.1194C>T) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Ile398= (c.1194C>T) in the general population?

LDLR p.Ile398= (c.1194C>T) is low-frequency (popmax 1.66%, eas) (gnomAD).

LDLR p.Ile398=

c.1194C>T · rs13306498 · VCV224620

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 18 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.66%, eas)

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

Likely Benign for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):

BS1 BP7 BP4

Curation rationale (ClinGen, verbatim)

The NM_000527.5(LDLR): c.1194C>T (p.Ile398=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 22 July 2022. The supporting evidence is as follows: BS1 - FAF = 0.00448 (0.448%) in East Asian exomes (gnomAD v2.1.1). BP4 - No REVEL, splicing evaluation required. Functional data on splicing not available. Variant is not located within the limits of canonical splicing sites Variant is exonic and at least 50bp upstream from canonical donor site but does not creates AG There is no AG Nearby Variant is not predicted to alter splicing. BP7 - Variant is synonymous and meets BP4

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 -8.2	GERP -3.8
Overall
CADD	6.406	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.66% East Asian · 746/44,878 alleles

Filtering AF 1.56% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.52%

Overall 0.123% 1,981/1,612,774 alleles · low-frequency exomes 1,745/1,460,576 · genomes 236/152,198 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	1.66%	60
Finnishnot grpmax-eligible	1.1%	91
Remaining individualsnot grpmax-eligible	0.0961%	1,040
South Asian	0.0626%	1,597
Middle Eastern	0.0373%	2,684
European (non-Finnish)	0.0337%	2,965
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,921
Admixed American	0.0167%	5,996

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.Ile398=
Coding: c.1194C>T
MANE Select: NM_000527
dbSNP: rs13306498
Type: single nucleotide variant
Location: chr19:11113285 (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 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
LDLR c.313+1G>A 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-ile398 (accessed [today's date]).

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