Is PPIC p.Thr116Ile (c.347C>T) pathogenic?

PPIC p.Thr116Ile (c.347C>T) is classified Uncertain significance in PPIC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-29). AlphaMissense: likely benign (0.2402); Very rare (popmax 0.00172%, amr).

How common is PPIC p.Thr116Ile (c.347C>T) in the general population?

PPIC p.Thr116Ile (c.347C>T) is very rare (popmax 0.00172%, amr) (gnomAD).

What do computational predictors say about PPIC p.Thr116Ile (c.347C>T)?

AlphaMissense predicts likely benign (score 0.2402) — an in-silico prediction, not a clinical call.

PPIC p.Thr116Ile

c.347C>T · VCV3936658

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2402 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00172%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2402	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -8.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 0.16, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 13 kb · p 0.97 · regional, not allelic
Overall
CADD	22.8	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 0.00172% Admixed American · 1/58,122 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.00056% 9/1,606,444 alleles · very rare exomes 5/1,454,348 · genomes 4/152,096 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00172%	58,122
African / African-American	0.00134%	74,484
European (non-Finnish)	0.000594%	168,230

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: PPIC
Protein: p.Thr116Ile
Coding: c.347C>T
MANE Select: NM_000943
Type: single nucleotide variant
Location: chr5:123025947 (GRCh38)
Gene constraint: LOEUF 1.354 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.88 · 1 PDB
Residue 116: the ppiase cyclophilin-type domain

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

Similar variants

PPIC p.Ala137Thr Uncertain significance ★ ⚠ same type
PPIC p.Ala19Val Uncertain significance ★ ⚠ same type
PPIC p.Ala210Thr Uncertain significance ★ ⚠ same type
PPIC p.Arg6Gln Uncertain significance ★ ⚠ same type
PPIC p.Asp185Glu Uncertain significance ★ ⚠ same type
PPIC p.Asp200Gly Uncertain significance ★ ⚠ same type
PPIC p.Glu115Asp Uncertain significance ★ ⚠ same type
PPIC p.Gly130Glu 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/ppic-p-thr116ile (accessed [today's date]).

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