Is PPIG p.Ser677Ile (c.2030G>T) pathogenic?

PPIG p.Ser677Ile (c.2030G>T) is classified Uncertain significance in PPIG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely benign (0.0814); Very rare (popmax 0.00902%, sas).

How common is PPIG p.Ser677Ile (c.2030G>T) in the general population?

PPIG p.Ser677Ile (c.2030G>T) is very rare (popmax 0.00902%, sas) (gnomAD).

What do computational predictors say about PPIG p.Ser677Ile (c.2030G>T)?

AlphaMissense predicts likely benign (score 0.0814) — an in-silico prediction, not a clinical call.

PPIG p.Ser677Ile

c.2030G>T · VCV4570844

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0814 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00902%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0814	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -8.08	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.68	GERP -0.54, phastCons 0.68
Regional constraint	o/e 0.99	unconstrained · MANE · 4,277 bp · p 0.75 · regional, not allelic
Overall
CADD	18.43	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

Grpmax group 0.00902% South Asian · 8/88,710 alleles

Filtering AF 0.00447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00319%

Overall 0.000498% 8/1,604,978 alleles · very rare exomes 8/1,452,966 · genomes 0/152,012 · joint denominator

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.Ser677Ile
Coding: c.2030G>T
MANE Select: NM_004792
Type: single nucleotide variant
Location: chr2:169637288 (GRCh38)
Gene constraint: LOEUF 0.472 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.64 · 4 PDB
Residue 677: 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-ser677ile (accessed [today's date]).

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