Is LDLR p.Cys231= (c.693C>T) pathogenic?

LDLR p.Cys231= (c.693C>T) is classified Conflicting classifications of pathogenicity in LDLR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-03-11). Ultra-rare (popmax 0.0211%, eas); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Cys231= (c.693C>T)?

LDLR p.Cys231= (c.693C>T) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Cys231= (c.693C>T) in the general population?

LDLR p.Cys231= (c.693C>T) is ultra-rare (popmax 0.0211%, eas) (gnomAD).

LDLR p.Cys231=

c.693C>T · rs121908035 · VCV2773501

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0211%, eas)

Conditions

hypercholesterolemia, familial, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.41	donor gain · deltas
Constraint at this position
Conservation	phyloP -3.8	GERP -5.1
Overall
CADD	12.73	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0211% East Asian · 8/37,880 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00762%

Overall 0.00067% 9/1,344,208 alleles · ultra-rare exomes 9/1,194,076 · genomes 0/150,132 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0211%	4,735
Remaining individualsnot grpmax-eligible	0.00195%	51,268

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.Cys231=
Coding: c.693C>T
MANE Select: NM_000527
dbSNP: rs121908035
Type: single nucleotide variant
Location: chr19:11105599 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 231: a UniProt-annotated variant site (in fhcl1); the 'binding to getah virus e1-e2 spike glycoproteins' region; a disulfide bond; the ldl-receptor class a 5 domain

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.Cys231Trp Likely pathogenic ★★★ same residue
LDLR p.Cys231Arg Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys231Gly Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys231Ter Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys231Tyr 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

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-cys231 (accessed [today's date]).

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