Is LDLR p.Cys89= (c.267C>T) pathogenic?

LDLR p.Cys89= (c.267C>T) is classified Likely benign in LDLR (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-11-13). Ultra-rare (popmax 0.02%, afr); Associated with Cardiovascular phenotype.

What condition is associated with LDLR p.Cys89= (c.267C>T)?

LDLR p.Cys89= (c.267C>T) is associated with Cardiovascular phenotype, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Cys89= (c.267C>T) in the general population?

LDLR p.Cys89= (c.267C>T) is ultra-rare (popmax 0.02%, afr) (gnomAD).

LDLR p.Cys89=

c.267C>T · rs777640882 · VCV496024

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP -3.1	GERP -5.1
Overall
CADD	3.195	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% African / African-American · 15/74,912 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00989%

Overall 0.00124% 20/1,613,794 alleles · ultra-rare exomes 9/1,461,664 · genomes 11/152,130 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.02%	4,994
South Asian	0.0011%	91,084
European (non-Finnish)	0.000339%	294,974

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.Cys89=
Coding: c.267C>T
MANE Select: NM_000527
dbSNP: rs777640882
Type: single nucleotide variant
Location: chr19:11102740 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 89: a disulfide bond; the ldl-receptor class a 2 domain; a UniProt-annotated variant site (in fhcl1)

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.Cys89Arg Likely pathogenic ★★★ same residue
LDLR p.Cys89Gly Likely pathogenic ★★ same residue
LDLR p.Cys89Trp Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys89Tyr 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

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-cys89 (accessed [today's date]).

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