Is PPIE p.Ser138Pro (c.412T>C) pathogenic?

PPIE p.Ser138Pro (c.412T>C) is classified Uncertain significance in PPIE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-30). AlphaMissense: likely benign (0.0913); Very rare (popmax 0.000424%, nfe).

How common is PPIE p.Ser138Pro (c.412T>C) in the general population?

PPIE p.Ser138Pro (c.412T>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about PPIE p.Ser138Pro (c.412T>C)?

AlphaMissense predicts likely benign (score 0.0913) — an in-silico prediction, not a clinical call.

PPIE p.Ser138Pro

c.412T>C · VCV4142411

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0913 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0913	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -4.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.56 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.5	GERP 0.79, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 14 kb · p 0.0012 · regional, not allelic
Overall
CADD	19.61	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,180,052 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,096 alleles · very rare exomes 2/1,461,880 · genomes 3/152,216 · 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: PPIE
Protein: p.Ser138Pro
Coding: c.412T>C
MANE Select: NM_006112
Type: single nucleotide variant
Location: chr1:39745402 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.11 · 40 PDB
Residue 138: an α-helix

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

Similar variants

BMP8B p.Ala368Val Uncertain significance ★ ⚠ same type
PPIE p.Ala57Val Uncertain significance ★ ⚠ same type
PPIE p.Arg137Cys Uncertain significance ★ ⚠ same type
PPIE p.Arg161Cys Uncertain significance ★ ⚠ same type
PPIE p.Arg173His Uncertain significance ★ ⚠ same type
PPIE p.Arg276Trp Uncertain significance ★ ⚠ same type
PPIE p.Arg78His Uncertain significance ★ ⚠ same type
PPIE p.Asn207Ser 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/ppie-p-ser138pro (accessed [today's date]).

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