Is LDLR p.Pro795His (c.2384C>A) pathogenic?

LDLR p.Pro795His (c.2384C>A) is classified Conflicting classifications of pathogenicity in LDLR (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2016-03-25). AlphaMissense: likely pathogenic (0.7952); Very rare (popmax 8.47e-05%, nfe); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Pro795His (c.2384C>A)?

LDLR p.Pro795His (c.2384C>A) is associated with hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Pro795His (c.2384C>A) in the general population?

LDLR p.Pro795His (c.2384C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about LDLR p.Pro795His (c.2384C>A)?

AlphaMissense predicts likely pathogenic (score 0.7952) — an in-silico prediction, not a clinical call.

LDLR p.Pro795His

c.2384C>A · rs879255184 · VCV252296

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7952 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypercholesterolemia, familial, 1

Computational evidence

Protein change
AlphaMissense	0.7952	likely pathogenic
REVEL	0.735	pathogenic-leaning
SaProt	LLR -17.27	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 4.5	GERP 0.34, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	23.9	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,946 alleles

Overall 6.2e-05% 1/1,614,034 alleles · very rare exomes 1/1,461,760 · genomes 0/152,274 · joint denominator

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.Pro795His
Coding: c.2384C>A
MANE Select: NM_000527
dbSNP: rs879255184
Type: single nucleotide variant
Location: chr19:11128080 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB

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.Pro795Arg Uncertain significance ★ ⚠ 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
LDLR c.2140+1G>A Pathogenic ★★★ same condition
LDLR c.2389+2T>G 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-pro795his (accessed [today's date]).

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