Is ADAM17 p.Pro425Leu (c.1274C>T) pathogenic?

ADAM17 p.Pro425Leu (c.1274C>T) is classified Uncertain significance in ADAM17 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-04-12). AlphaMissense: likely pathogenic (0.9725); Very rare (popmax 0.000339%, nfe); Associated with inflammatory skin and bowel disease, neonatal, 1.

What condition is associated with ADAM17 p.Pro425Leu (c.1274C>T)?

ADAM17 p.Pro425Leu (c.1274C>T) is associated with inflammatory skin and bowel disease, neonatal, 1 (ClinVar).

How common is ADAM17 p.Pro425Leu (c.1274C>T) in the general population?

ADAM17 p.Pro425Leu (c.1274C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about ADAM17 p.Pro425Leu (c.1274C>T)?

AlphaMissense predicts likely pathogenic (score 0.9725) — an in-silico prediction, not a clinical call.

ADAM17 p.Pro425Leu

Q: How is Neonatal erythroderma-autoinflammation-inflammatory bowel disease syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1274C>T · rs1663648695 · VCV1060528

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9725 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inflammatory skin and bowel disease, neonatal, 1

Computational evidence

Protein change
AlphaMissense	0.9725	likely pathogenic
REVEL	0.645	pathogenic-leaning
SaProt	LLR -13.52	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 43 kb · p 2.2e-17 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000339% European (non-Finnish) · 4/1,179,980 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,834 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: ADAM17
Protein: p.Pro425Leu
Coding: c.1274C>T
MANE Select: NM_003183
dbSNP: rs1663648695
Type: single nucleotide variant
Location: chr2:9510049 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 72.72 · 33 PDB
Residue 425: a disulfide bond; the peptidase m12b domain

Full ADAM17 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

inflammatory skin and bowel disease, neonatal, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Neonatal erythroderma-autoinflammation-inflammatory bowel disease syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ADAM17 p.Pro425= Likely benign ★ same residue
ADAM17 p.Arg651Ter Pathogenic/Likely pathogenic ★★ same condition
ADAM17 p.Ala742Thr Uncertain significance ★★ ⚠ same condition
ADAM17 p.Ala806Pro Uncertain significance ★★ ⚠ same condition
ADAM17 p.Ala806Ser Uncertain significance ★★ ⚠ same condition
ADAM17 p.Arg132Lys Uncertain significance ★★ ⚠ same condition
ADAM17 p.Arg177His Uncertain significance ★★ ⚠ same condition
ADAM17 p.Arg738Cys Uncertain significance ★★ ⚠ same condition

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/adam17-p-pro425leu (accessed [today's date]).

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