Is PLTP p.Arg394Pro (c.1181G>C) pathogenic?

PLTP p.Arg394Pro (c.1181G>C) is classified Uncertain significance in PLTP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-12). AlphaMissense: likely pathogenic (0.8249); Very rare (popmax 0.00259%, amr).

How common is PLTP p.Arg394Pro (c.1181G>C) in the general population?

PLTP p.Arg394Pro (c.1181G>C) is very rare (popmax 0.00259%, amr) (gnomAD).

What do computational predictors say about PLTP p.Arg394Pro (c.1181G>C)?

AlphaMissense predicts likely pathogenic (score 0.8249) — an in-silico prediction, not a clinical call.

PLTP p.Arg394Pro

c.1181G>C · VCV3307872

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8249 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00259%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8249	likely pathogenic
REVEL	0.168	moderately benign-leaning
SaProt	LLR -12.39	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.24	donor loss · deltas
Constraint at this position
Conservation	phyloP 6	GERP 0.034, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 13 kb · p 0.099 · regional, not allelic
Overall
CADD	28.0	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 0.00259% Admixed American · 1/38,540 alleles

Overall 0.000842% 1/118,730 alleles · very rare

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: PLTP
Protein: p.Arg394Pro
Coding: c.1181G>C
MANE Select: NM_006227
Type: single nucleotide variant
Location: chr20:45899873 (GRCh38)
Gene constraint: LOEUF 1.002 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.36

Full PLTP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLTP p.Arg394Ter Uncertain significance ★ same residue
PLTP p.Ala155Thr Uncertain significance ★★ ⚠ same type
PLTP p.Ala155Val Uncertain significance ★★ ⚠ same type
PLTP p.Arg177Cys Uncertain significance ★★ ⚠ same type
PLTP p.Arg251Gln Uncertain significance ★★ ⚠ same type
PLTP p.Arg372His Uncertain significance ★★ ⚠ same type
PLTP p.Arg380Gln Uncertain significance ★★ ⚠ same type
PLTP p.Arg391Cys Uncertain significance ★★ ⚠ same type

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/pltp-p-arg394pro (accessed [today's date]).

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