Is LDLR p.Cys352Ser (c.1054T>A) pathogenic?

LDLR p.Cys352Ser (c.1054T>A) is classified Likely pathogenic in LDLR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2017-05-24). AlphaMissense: likely pathogenic (0.9975); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with LDLR p.Cys352Ser (c.1054T>A)?

LDLR p.Cys352Ser (c.1054T>A) is associated with Cardiovascular phenotype, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Cys352Ser (c.1054T>A) in the general population?

LDLR p.Cys352Ser (c.1054T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDLR p.Cys352Ser (c.1054T>A)?

AlphaMissense predicts likely pathogenic (score 0.9975) — an in-silico prediction, not a clinical call.

LDLR p.Cys352Ser

c.1054T>A · rs879254769 · VCV251617

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9975 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9975	likely pathogenic ✓ concordant with ClinVar · top 1% in LDLR
REVEL	0.983	strongly pathogenic-leaning
SaProt	LLR -14.20	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: LDLR
Protein: p.Cys352Ser
Coding: c.1054T>A
MANE Select: NM_000527
dbSNP: rs879254769
Type: single nucleotide variant
Location: chr19:11110765 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 352: the egf-like 1 domain; a UniProt-annotated variant site (in fhcl1; uncertain significance); a UniProt-annotated variant site (in fhcl1; likely pathogenic; mexico-2); a β-strand; a disulfide bond

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: hypercholesterolemia, familial, 1

Similar variants

LDLR p.Cys352Tyr Likely pathogenic ★★★ same residue
LDLR p.Cys352= Benign ★★★ same residue
LDLR p.Cys352Arg Likely pathogenic ★★ same residue
LDLR p.Cys352Phe Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys352Ter Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys352Trp Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys352del Likely pathogenic ★ same residue
LDLR p.Cys352fs Pathogenic ★ same residue

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-cys352ser (accessed [today's date]).

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