Is PADI2 p.Pro366Ala (c.1096C>G) pathogenic?

PADI2 p.Pro366Ala (c.1096C>G) is classified Uncertain significance in PADI2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.2112); Very rare (popmax 0.00168%, amr).

How common is PADI2 p.Pro366Ala (c.1096C>G) in the general population?

PADI2 p.Pro366Ala (c.1096C>G) is very rare (popmax 0.00168%, amr) (gnomAD).

What do computational predictors say about PADI2 p.Pro366Ala (c.1096C>G)?

AlphaMissense predicts likely benign (score 0.2112) — an in-silico prediction, not a clinical call.

PADI2 p.Pro366Ala

c.1096C>G · VCV4130061

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2112 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2112	likely benign
REVEL	0.238	benign-leaning
SaProt	LLR -10.53	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 50 kb · p 0.22 · regional, not allelic
Overall
CADD	24.0	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 0.00168% Admixed American · 1/59,378 alleles

Overall 0.000658% 1/152,014 alleles · very rare

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: PADI2
Protein: p.Pro366Ala
Coding: c.1096C>G
MANE Select: NM_007365
Type: single nucleotide variant
Location: chr1:17082607 (GRCh38)
Gene constraint: LOEUF 1.325 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.35 · 24 PDB
Residue 366: a β-strand

Full PADI2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PADI2 p.Ala149Thr Uncertain significance ★★ ⚠ same type
PADI2 p.Arg233Gln Likely benign ★★ same type
PADI2 p.His471= Benign ★★ same type
PADI2 p.Leu627= Benign ★★ same type
PADI2 p.Pro624= Benign ★★ same type
PADI2 p.Thr114= Benign ★★ same type
PADI2 p.Tyr241= Benign ★★ same type
PADI2 p.Ala138Thr 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/padi2-p-pro366ala (accessed [today's date]).

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