Is LDLR p.Thr491= (c.1473C>T) pathogenic?

LDLR p.Thr491= (c.1473C>T) is classified Likely benign in LDLR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-04). Very rare (popmax 0.00267%, afr); Associated with Cardiovascular phenotype.

What condition is associated with LDLR p.Thr491= (c.1473C>T)?

LDLR p.Thr491= (c.1473C>T) is associated with Cardiovascular phenotype, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Thr491= (c.1473C>T) in the general population?

LDLR p.Thr491= (c.1473C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

LDLR p.Thr491=

c.1473C>T · rs558238642 · VCV1623346

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

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 -20	GERP -5.1
Overall
CADD	2.175	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/75,022 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000434% 7/1,613,830 alleles · very rare exomes 3/1,461,586 · genomes 4/152,244 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,511
East Asian	0.00223%	44,880
Admixed American	0.00167%	60,012
European (non-Finnish)	0.000254%	393,255

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.Thr491=
Coding: c.1473C>T
MANE Select: NM_000527
dbSNP: rs558238642
Type: single nucleotide variant
Location: chr19:11113649 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 491: a β-strand

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

Similar variants

LDLR p.Thr491Ala Uncertain significance ★ ⚠ same residue
LDLR p.Thr491Asn 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.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-thr491 (accessed [today's date]).

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