Is ADAM17 p.Ser266Pro (c.796T>C) pathogenic?

ADAM17 p.Ser266Pro (c.796T>C) is classified Uncertain significance in ADAM17 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-01-27). AlphaMissense: ambiguous (0.5059); Absent from gnomAD v4.1; Associated with inflammatory skin and bowel disease, neonatal, 1.

What condition is associated with ADAM17 p.Ser266Pro (c.796T>C)?

ADAM17 p.Ser266Pro (c.796T>C) is associated with inflammatory skin and bowel disease, neonatal, 1 (ClinVar).

How common is ADAM17 p.Ser266Pro (c.796T>C) in the general population?

ADAM17 p.Ser266Pro (c.796T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ADAM17 p.Ser266Pro (c.796T>C)?

AlphaMissense predicts ambiguous (score 0.5059) — an in-silico prediction, not a clinical call.

ADAM17 p.Ser266Pro

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.796T>C · rs1664383899 · VCV1017252

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5059 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

inflammatory skin and bowel disease, neonatal, 1

Computational evidence

Protein change
AlphaMissense	0.5059	ambiguous
REVEL	0.601	indeterminate
SaProt	LLR -8.48	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 43 kb · p 2.2e-17 · regional, not allelic
Overall
CADD	24.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ADAM17
Protein: p.Ser266Pro
Coding: c.796T>C
MANE Select: NM_003183
dbSNP: rs1664383899
Type: single nucleotide variant
Location: chr2:9523296 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 72.72 · 33 PDB
Residue 266: 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.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
ADAM17 p.Arg813His 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-ser266pro (accessed [today's date]).

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