Is PADI2 p.Pro425Leu (c.1274C>T) pathogenic?

PADI2 p.Pro425Leu (c.1274C>T) is classified Uncertain significance in PADI2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-20). AlphaMissense: ambiguous (0.402); Very rare (popmax 0.000424%, nfe).

How common is PADI2 p.Pro425Leu (c.1274C>T) in the general population?

PADI2 p.Pro425Leu (c.1274C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about PADI2 p.Pro425Leu (c.1274C>T)?

AlphaMissense predicts ambiguous (score 0.402) — an in-silico prediction, not a clinical call.

PADI2 p.Pro425Leu

c.1274C>T · VCV3413228

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.402 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.402	ambiguous
REVEL	0.669	pathogenic-leaning
SaProt	LLR -8.39	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 10	GERP 2.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 50 kb · p 0.22 · regional, not allelic
Overall
CADD	28.2	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 0.000424% European (non-Finnish) · 5/1,179,986 alleles

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

Overall 0.00031% 5/1,614,106 alleles · very rare exomes 5/1,461,808 · genomes 0/152,298 · 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: PADI2
Protein: p.Pro425Leu
Coding: c.1274C>T
MANE Select: NM_007365
Type: single nucleotide variant
Location: chr1:17079300 (GRCh38)
Gene constraint: LOEUF 1.325 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.35 · 24 PDB

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-pro425leu (accessed [today's date]).

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