Is LDLR p.Thr389= (c.1167G>A) pathogenic?

LDLR p.Thr389= (c.1167G>A) is classified Likely benign in LDLR (ClinVar, Expert panel, 13 submitters; last evaluated 2023-03-20). Rare (popmax 0.224%, afr); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Thr389= (c.1167G>A)?

LDLR p.Thr389= (c.1167G>A) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Thr389= (c.1167G>A) in the general population?

LDLR p.Thr389= (c.1167G>A) is rare (popmax 0.224%, afr) (gnomAD).

LDLR p.Thr389=

c.1167G>A · rs139066906 · VCV256365

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

rare (popmax 0.224%, afr)

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

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

BP7 BP4

Curation rationale (ClinGen, verbatim)

The NM_000527.5(LDLR):c.1167G>A (p.Thr389=) variant is classified as likely benign for Familial Hypercholesterolemia by applying evidence codes: BP4, BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BP4 - No REVEL, splicing evaluation needed. Functional data on splicing not available. A) not on limits B) does not create GT 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 0.33	GERP -1.9, phastCons 0.12
Overall
CADD	12.98	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.224% African / African-American · 168/75,070 alleles

Filtering AF 0.196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.186%

Overall 0.0143% 230/1,613,640 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.224%	447
Middle Eastern	0.066%	1,516
Remaining individualsnot grpmax-eligible	0.0416%	2,404
Admixed American	0.0167%	6,003
South Asian	0.00659%	15,180
European (non-Finnish)	0.00136%	73,744

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.Thr389=
Coding: c.1167G>A
MANE Select: NM_000527
dbSNP: rs139066906
Type: single nucleotide variant
Location: chr19:11111620 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 389: the egf-like 2; calcium-binding domain; a turn; a disulfide bond

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.Thr389Ala Likely pathogenic ★ ⚠ same residue
LDLR p.Thr389Lys Likely pathogenic ★ ⚠ same residue
LDLR p.Thr389Arg Uncertain significance ★ ⚠ same residue
LDLR p.Thr389Met Conflicting classifications of pathogenicity ★ ⚠ 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

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-thr389 (accessed [today's date]).

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