Is LDLR p.Phe153Ser (c.458T>C) pathogenic?

LDLR p.Phe153Ser (c.458T>C) is classified Uncertain significance in LDLR (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-04). AlphaMissense: likely pathogenic (0.9665); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with LDLR p.Phe153Ser (c.458T>C)?

LDLR p.Phe153Ser (c.458T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is LDLR p.Phe153Ser (c.458T>C) in the general population?

LDLR p.Phe153Ser (c.458T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDLR p.Phe153Ser (c.458T>C)?

AlphaMissense predicts likely pathogenic (score 0.9665) — an in-silico prediction, not a clinical call.

LDLR p.Phe153Ser

c.458T>C · VCV4825488

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9665 · 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	0.9665	likely pathogenic
REVEL	0.943	strongly pathogenic-leaning
SaProt	LLR -18.54	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 4.9	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Phe153Ser
Coding: c.458T>C
MANE Select: NM_000527
Type: single nucleotide variant
Location: chr19:11105364 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 153: the 'binding to getah virus e1-e2 spike glycoproteins' region; a β-strand; the ldl-receptor class a 4 domain

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

Similar variants

LDLR p.Phe153Val Likely pathogenic ★★ same residue
LDLR p.Phe153Cys Likely pathogenic ★ same residue
LDLR p.Phe153Leu Likely pathogenic ★ same residue
LDLR c.1061-1G>C Pathogenic/Likely pathogenic ★★ same condition
LDLR c.1186+1G>T Pathogenic ★★ same condition
LDLR c.1186+2T>G Pathogenic/Likely pathogenic ★★ same condition
LDLR c.1586+1G>A Pathogenic/Likely pathogenic ★★ same condition
LDLR c.1587-1G>A Pathogenic/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-phe153ser (accessed [today's date]).

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