Is PPIG p.Arg669Cys (c.2005C>T) pathogenic?

PPIG p.Arg669Cys (c.2005C>T) is classified Uncertain significance in PPIG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). AlphaMissense: likely benign (0.1591); Very rare (popmax 0.00771%, sas).

How common is PPIG p.Arg669Cys (c.2005C>T) in the general population?

PPIG p.Arg669Cys (c.2005C>T) is very rare (popmax 0.00771%, sas) (gnomAD).

What do computational predictors say about PPIG p.Arg669Cys (c.2005C>T)?

AlphaMissense predicts likely benign (score 0.1591) — an in-silico prediction, not a clinical call.

PPIG p.Arg669Cys

c.2005C>T · VCV4570838

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1591 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00771%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1591	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -10.27	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 4,277 bp · p 0.75 · regional, not allelic
Overall
CADD	23.9	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 0.00771% South Asian · 7/90,806 alleles

Filtering AF 0.0036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00136% 22/1,612,412 alleles · very rare exomes 20/1,460,512 · genomes 2/151,900 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00771%	12,972
Remaining individualsnot grpmax-eligible	0.0032%	31,208
Finnishnot grpmax-eligible	0.00157%	63,770
European (non-Finnish)	0.00102%	98,306

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: PPIG
Protein: p.Arg669Cys
Coding: c.2005C>T
MANE Select: NM_004792
Type: single nucleotide variant
Location: chr2:169637263 (GRCh38)
Gene constraint: LOEUF 0.472 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.64 · 4 PDB
Residue 669: the 'disordered' region

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

Similar variants

PPIG p.Arg669His Uncertain significance ★ ⚠ same residue
PPIG c.929+11A>G Benign ★★ same type
PPIG p.Asn672= Benign ★★ same type
PPIG p.Glu495= Benign ★★ same type
PPIG p.Thr54= Benign ★★ same type
PPIG p.Ala542Thr Uncertain significance ★ ⚠ same type
PPIG p.Arg235Gln Uncertain significance ★ ⚠ same type
PPIG p.Arg239Gln 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/ppig-p-arg669cys (accessed [today's date]).

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