Is LDLR p.Thr659= (c.1977C>A) pathogenic?

LDLR p.Thr659= (c.1977C>A) is classified Benign/Likely benign in LDLR (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-03-01). Ultra-rare (popmax 0.085%, amr); Associated with Cardiovascular phenotype.

What condition is associated with LDLR p.Thr659= (c.1977C>A)?

LDLR p.Thr659= (c.1977C>A) is associated with Cardiovascular phenotype, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Thr659= (c.1977C>A) in the general population?

LDLR p.Thr659= (c.1977C>A) is ultra-rare (popmax 0.085%, amr) (gnomAD).

LDLR p.Thr659=

c.1977C>A · rs72658866 · VCV252142

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.085%, amr)

Conditions

Cardiovascular phenotype

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 -11	GERP -4.4
Overall
CADD	0.011	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.085% Admixed American · 51/60,004 alleles

Filtering AF 0.0664% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0598%

Overall 0.0409% 660/1,614,164 alleles · ultra-rare exomes 611/1,461,874 · genomes 49/152,290 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.085%	1,177
European (non-Finnish)	0.0488%	2,049
Remaining individualsnot grpmax-eligible	0.04%	2,500
South Asian	0.00439%	22,772
African / African-American	0.004%	25,013
Finnishnot grpmax-eligible	0.00156%	64,036

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.Thr659=
Coding: c.1977C>A
MANE Select: NM_000527
dbSNP: rs72658866
Type: single nucleotide variant
Location: chr19:11120223 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 659: an α-helix

Full LDLR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypercholesterolemia hypercholesterolemia, familial, 1

Similar variants

LDLR p.Thr659Pro Likely pathogenic ★★★ same residue
LDLR p.Thr659Asn Uncertain significance ★★★ ⚠ same residue
LDLR p.Thr659Ile 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

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-thr659 (accessed [today's date]).

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