Is PPID p.Arg49Pro (c.146G>C) pathogenic?

PPID p.Arg49Pro (c.146G>C) is classified Uncertain significance in PPID (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: likely pathogenic (0.9624); Very rare (popmax 0.0011%, sas).

How common is PPID p.Arg49Pro (c.146G>C) in the general population?

PPID p.Arg49Pro (c.146G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about PPID p.Arg49Pro (c.146G>C)?

AlphaMissense predicts likely pathogenic (score 0.9624) — an in-silico prediction, not a clinical call.

PPID p.Arg49Pro

c.146G>C · rs369501739 · VCV3217189

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9624 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9624	likely pathogenic · top 1% in PPID
REVEL	0.296	indeterminate
SaProt	LLR -17.52	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 4.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 14 kb · p 0.49 · regional, not allelic
Overall
CADD	29.3	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 0.0011% South Asian · 1/91,078 alleles

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

Overall 0.000372% 6/1,613,914 alleles · very rare exomes 5/1,461,794 · genomes 1/152,120 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,078
European (non-Finnish)	0.000424%	235,992

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: PPID
Protein: p.Arg49Pro
Coding: c.146G>C
MANE Select: NM_005038
dbSNP: rs369501739
Type: single nucleotide variant
Location: chr4:158721423 (GRCh38)
Gene constraint: LOEUF 1.303 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.51
Residue 49: a UniProt-annotated variant site (in); the ppiase cyclophilin-type domain

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

Similar variants

PPID p.Arg49His Uncertain significance ★ ⚠ same residue
PPID p.Val177Ile Benign ★★ same type
PPID p.Ala299Pro Uncertain significance ★ ⚠ same type
PPID p.Ala326Thr Uncertain significance ★ ⚠ same type
PPID p.Ala356Thr Uncertain significance ★ ⚠ same type
PPID p.Arg125His Uncertain significance ★ ⚠ same type
PPID p.Arg312Cys Uncertain significance ★ ⚠ same type
PPID p.Arg312His 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/ppid-p-arg49pro (accessed [today's date]).

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