Is PPIC p.Ala137Thr (c.409G>A) pathogenic?

PPIC p.Ala137Thr (c.409G>A) is classified Uncertain significance in PPIC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: ambiguous (0.3663); Very rare (popmax 0.00446%, eas).

How common is PPIC p.Ala137Thr (c.409G>A) in the general population?

PPIC p.Ala137Thr (c.409G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about PPIC p.Ala137Thr (c.409G>A)?

AlphaMissense predicts ambiguous (score 0.3663) — an in-silico prediction, not a clinical call.

PPIC p.Ala137Thr

c.409G>A · VCV3936651

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3663 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3663	ambiguous
REVEL	0.212	benign-leaning
SaProt	LLR -11.32	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 6.1	GERP 2.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 13 kb · p 0.97 · regional, not allelic
Overall
CADD	24.8	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

Grpmax group 0.00446% East Asian · 2/44,868 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000372% 6/1,614,048 alleles · very rare exomes 6/1,461,772 · genomes 0/152,276 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,434
South Asian	0.0011%	91,034
European (non-Finnish)	0.000254%	393,334

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.Ala137Thr
Coding: c.409G>A
MANE Select: NM_000943
Type: single nucleotide variant
Location: chr5:123025885 (GRCh38)
Gene constraint: LOEUF 1.354 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.88 · 1 PDB
Residue 137: the ppiase cyclophilin-type domain; a β-strand

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

Similar variants

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
PPIC p.Gly25Ala 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-ala137thr (accessed [today's date]).

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