Is LDLR p.Pro84Ser (c.250C>T) pathogenic?

LDLR p.Pro84Ser (c.250C>T) is classified Uncertain significance in LDLR (ClinVar, Expert panel, 3 submitters; last evaluated 2023-03-20). AlphaMissense: ambiguous (0.5357); Absent from gnomAD v4.1; Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Pro84Ser (c.250C>T)?

LDLR p.Pro84Ser (c.250C>T) is associated with hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Pro84Ser (c.250C>T) in the general population?

LDLR p.Pro84Ser (c.250C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LDLR p.Pro84Ser (c.250C>T)?

AlphaMissense predicts ambiguous (score 0.5357) — an in-silico prediction, not a clinical call.

LDLR p.Pro84Ser

c.250C>T · rs879254449 · VCV251094

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5357 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):

PM2 PP4

Curation rationale (ClinGen, verbatim)

The NM_000527.5(LDLR):c.250C>T (p.Pro84Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PP4 - Variant meets PM2 and is identified in one index case who fulfill FH/DLCN>=6 criteria for FH from PMID 11810272

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.5357	ambiguous
REVEL	0.622	indeterminate
SaProt	LLR -8.89	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.17	GERP -1.4
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	17.67	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.Pro84Ser
Coding: c.250C>T
MANE Select: NM_000527
dbSNP: rs879254449
Type: single nucleotide variant
Location: chr19:11102723 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 84: the ldl-receptor class a 2 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

Similar variants

LDLR p.Pro84Arg Uncertain significance ★★★ ⚠ same residue
LDLR p.Pro84Leu Uncertain significance ★★★ ⚠ same residue
LDLR p.Pro84fs 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
LDLR c.1705+2T>C Likely pathogenic ★★★ same condition
LDLR c.190+4A>T 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-pro84ser (accessed [today's date]).

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