Is ADAM17 p.Ser747fs (c.2237dup) pathogenic?

ADAM17 p.Ser747fs (c.2237dup) is classified Uncertain significance in ADAM17 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-04). Very rare (popmax 0.000932%, nfe); Associated with inflammatory skin and bowel disease, neonatal, 1.

What condition is associated with ADAM17 p.Ser747fs (c.2237dup)?

ADAM17 p.Ser747fs (c.2237dup) is associated with inflammatory skin and bowel disease, neonatal, 1 (ClinVar).

How common is ADAM17 p.Ser747fs (c.2237dup) in the general population?

ADAM17 p.Ser747fs (c.2237dup) is very rare (popmax 0.000932%, nfe) (gnomAD).

ADAM17 p.Ser747fs

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.2237dup · rs1662030392 · VCV1514442

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Conditions

inflammatory skin and bowel disease, neonatal, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -9.9	GERP -4.8

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000932% European (non-Finnish) · 11/1,180,018 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000821% 12/1,461,888 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)grpmax	0.000932%	107,274

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser747fs
Coding: c.2237dup
MANE Select: NM_001039613 · reported on NM_003183
dbSNP: rs1662030392
Type: Duplication
Location: chr2:9490414 (GRCh38)

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

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-ser747fs (accessed [today's date]).

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