Is PPIB p.Ser139Ile (c.416G>T) pathogenic?

PPIB p.Ser139Ile (c.416G>T) is classified Uncertain significance in PPIB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-01). AlphaMissense: likely pathogenic (0.9985); Absent from gnomAD v4.1.

How common is PPIB p.Ser139Ile (c.416G>T) in the general population?

PPIB p.Ser139Ile (c.416G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PPIB p.Ser139Ile (c.416G>T)?

AlphaMissense predicts likely pathogenic (score 0.9985) — an in-silico prediction, not a clinical call.

PPIB p.Ser139Ile

c.416G>T · rs150146348 · VCV2012622

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9985 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9985	likely pathogenic · top 3% in PPIB
REVEL	0.634	indeterminate
SaProt	LLR -17.00	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 6,960 bp · p 0.77 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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: PPIB
Protein: p.Ser139Ile
Coding: c.416G>T
MANE Select: NM_000942
dbSNP: rs150146348
Type: single nucleotide variant
Location: chr15:64156837 (GRCh38)
Gene constraint: LOEUF 1.104 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.98 · 8 PDB
Residue 139: the ppiase cyclophilin-type domain; a β-strand

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

Similar variants

PPIB p.Ser139Asn Uncertain significance ★★ ⚠ same residue
PPIB c.344-1G>T Pathogenic/Likely pathogenic ★★ same type
PPIB c.-91A>C Uncertain significance ★★ same type
PPIB p.Ala15Thr Uncertain significance ★★ ⚠ same type
PPIB p.Arg7Ser Uncertain significance ★★ ⚠ same type
PPIB p.Asn75Ser Uncertain significance ★★ ⚠ same type
PPIB p.Glu183Ala Uncertain significance ★★ ⚠ same type
PPIB p.Gly39Trp 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/ppib-p-ser139ile (accessed [today's date]).

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