Is PPIL4 p.Arg476Pro (c.1427G>C) pathogenic?

PPIL4 p.Arg476Pro (c.1427G>C) is classified Uncertain significance in PPIL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: ambiguous (0.4636); Absent from gnomAD v4.1.

How common is PPIL4 p.Arg476Pro (c.1427G>C) in the general population?

PPIL4 p.Arg476Pro (c.1427G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PPIL4 p.Arg476Pro (c.1427G>C)?

AlphaMissense predicts ambiguous (score 0.4636) — an in-silico prediction, not a clinical call.

PPIL4 p.Arg476Pro

c.1427G>C · VCV4570861

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4636 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4636	ambiguous
REVEL	0.136	moderately benign-leaning
SaProt	LLR -11.54	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.59, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 41 kb · p 8.5e-06 · regional, not allelic
Overall
CADD	22.0	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

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: PPIL4
Protein: p.Arg476Pro
Coding: c.1427G>C
MANE Select: NM_139126
Type: single nucleotide variant
Location: chr6:149505505 (GRCh38)
Gene constraint: LOEUF 1.088 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.56 · 7 PDB
Residue 476: the 'disordered' region

Full PPIL4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PPIL4 p.Arg476Gln Uncertain significance ★ ⚠ same residue
PPIL4 p.Ala297Thr Uncertain significance ★ ⚠ same type
PPIL4 p.Arg437Gln Uncertain significance ★ ⚠ same type
PPIL4 p.Arg445Gln Uncertain significance ★ ⚠ same type
PPIL4 p.Arg61Cys Uncertain significance ★ ⚠ same type
PPIL4 p.Asn240Tyr Uncertain significance ★ ⚠ same type
PPIL4 p.Asn38Asp Uncertain significance ★ ⚠ same type
PPIL4 p.Asn408Asp 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/ppil4-p-arg476pro (accessed [today's date]).

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