Is PPIG p.Ser666Pro (c.1996T>C) pathogenic?

PPIG p.Ser666Pro (c.1996T>C) is classified Uncertain significance in PPIG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-11). AlphaMissense: likely benign (0.1196); Absent from gnomAD v4.1.

How common is PPIG p.Ser666Pro (c.1996T>C) in the general population?

PPIG p.Ser666Pro (c.1996T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PPIG p.Ser666Pro (c.1996T>C)?

AlphaMissense predicts likely benign (score 0.1196) — an in-silico prediction, not a clinical call.

PPIG p.Ser666Pro

c.1996T>C · VCV4142423

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1196 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1196	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -9.08	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 5.1	GERP 0.57, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 4,277 bp · p 0.75 · regional, not allelic
Overall
CADD	23.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PPIG
Protein: p.Ser666Pro
Coding: c.1996T>C
MANE Select: NM_004792
Type: single nucleotide variant
Location: chr2:169637254 (GRCh38)
Gene constraint: LOEUF 0.472 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.64 · 4 PDB
Residue 666: the 'disordered' region

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

Similar variants

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
PPIG p.Arg350Lys 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-ser666pro (accessed [today's date]).

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