Is PPIC p.Val161Ala (c.482T>C) pathogenic?

PPIC p.Val161Ala (c.482T>C) is classified Uncertain significance in PPIC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-16). AlphaMissense: likely pathogenic (0.8475); Ultra-rare (popmax 0.0167%, amr).

How common is PPIC p.Val161Ala (c.482T>C) in the general population?

PPIC p.Val161Ala (c.482T>C) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about PPIC p.Val161Ala (c.482T>C)?

AlphaMissense predicts likely pathogenic (score 0.8475) — an in-silico prediction, not a clinical call.

PPIC p.Val161Ala

c.482T>C · VCV3423518

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8475 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8475	likely pathogenic
REVEL	0.614	indeterminate
SaProt	LLR -11.84	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 11	GERP 2.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 13 kb · p 0.97 · regional, not allelic
Overall
CADD	26.2	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

Grpmax group 0.0167% Admixed American · 10/59,928 alleles

Filtering AF 0.00901% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00682%

Overall 0.000806% 13/1,613,718 alleles · ultra-rare exomes 11/1,461,542 · genomes 2/152,176 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,993
Remaining individualsnot grpmax-eligible	0.0016%	62,472
European (non-Finnish)	0.000169%	589,984

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.Val161Ala
Coding: c.482T>C
MANE Select: NM_000943
Type: single nucleotide variant
Location: chr5:123025812 (GRCh38)
Gene constraint: LOEUF 1.354 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.88 · 1 PDB
Residue 161: 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-val161ala (accessed [today's date]).

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