Is LDLR p.Ser733Phe (c.2198C>T) pathogenic?

LDLR p.Ser733Phe (c.2198C>T) is classified Uncertain significance in LDLR (ClinVar, Single submitter, 1 submitter; last evaluated 2016-03-25). AlphaMissense: likely benign (0.1696); Absent from gnomAD v4.1; Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Ser733Phe (c.2198C>T)?

LDLR p.Ser733Phe (c.2198C>T) is associated with hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Ser733Phe (c.2198C>T) in the general population?

LDLR p.Ser733Phe (c.2198C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDLR p.Ser733Phe (c.2198C>T)?

AlphaMissense predicts likely benign (score 0.1696) — an in-silico prediction, not a clinical call.

LDLR p.Ser733Phe

c.2198C>T · rs879255162 · VCV252254

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1696 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hypercholesterolemia, familial, 1

Computational evidence

Protein change
AlphaMissense	0.1696	likely benign
REVEL	0.538	indeterminate
SaProt	LLR -10.09	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP 0.12
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	17.62	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.Ser733Phe
Coding: c.2198C>T
MANE Select: NM_000527
dbSNP: rs879255162
Type: single nucleotide variant
Location: chr19:11123231 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 733: the 'clustered o-linked oligosaccharides' region

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

Similar variants

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
LDLR c.190+4A>T Likely pathogenic ★★★ same condition
LDLR c.2140+1G>A Pathogenic ★★★ same condition
LDLR c.2389+2T>G Pathogenic ★★★ same condition
LDLR c.313+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-ser733phe (accessed [today's date]).

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