Is LDLR p.Cys134= (c.402C>T) pathogenic?

LDLR p.Cys134= (c.402C>T) is classified Likely benign in LDLR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-28). Very rare (popmax 0.000254%, nfe); Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Cys134= (c.402C>T)?

LDLR p.Cys134= (c.402C>T) is associated with familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Cys134= (c.402C>T) in the general population?

LDLR p.Cys134= (c.402C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

LDLR p.Cys134=

c.402C>T · rs879254515 · VCV440568

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

familial hypercholesterolemia

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 0.2	GERP -4.5, phastCons 0.009
Overall
CADD	5.304	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,030 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,796 alleles · very rare exomes 3/1,461,482 · genomes 0/152,314 · joint denominator

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.Cys134=
Coding: c.402C>T
MANE Select: NM_000527
dbSNP: rs879254515
Type: single nucleotide variant
Location: chr19:11105308 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 134: a disulfide bond; the ldl-receptor class a 3 domain; a UniProt-annotated variant site (in fhcl1)

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

Disease context

familial hypercholesterolemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypercholesterolemia, familial, 1

Similar variants

LDLR p.Cys134Arg Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys134Phe Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys134Tyr Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys134Trp Likely pathogenic ★ same residue
LDLR p.Cys134Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
LDLR p.Cys134Ser Pathogenic ★ same residue
LDLR c.1186+5G>A Likely pathogenic ★★★ same condition
LDLR c.1359-1G>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-cys134 (accessed [today's date]).

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