Is ADAM17 p.Ala439= (c.1317T>C) pathogenic?

ADAM17 p.Ala439= (c.1317T>C) is classified Benign/Likely benign in ADAM17 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-01). Rare (popmax 0.285%, eas); Associated with inflammatory skin and bowel disease, neonatal, 1.

What condition is associated with ADAM17 p.Ala439= (c.1317T>C)?

ADAM17 p.Ala439= (c.1317T>C) is associated with inflammatory skin and bowel disease, neonatal, 1 (ClinVar).

How common is ADAM17 p.Ala439= (c.1317T>C) in the general population?

ADAM17 p.Ala439= (c.1317T>C) is rare (popmax 0.285%, eas) (gnomAD).

ADAM17 p.Ala439=

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.1317T>C · rs200399376 · VCV733394

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.285%, eas)

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.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.21	GERP -4.4, phastCons 0.002
Overall
CADD	7.786	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.285% East Asian · 128/44,880 alleles

Filtering AF 0.245% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.23%

Overall 0.0101% 163/1,614,108 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.285%	351
Remaining individualsnot grpmax-eligible	0.048%	2,084
South Asian	0.00329%	30,357
Admixed American	0.00167%	60,018
European (non-Finnish)	8.47e-05%	1,179,986

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.Ala439=
Coding: c.1317T>C
MANE Select: NM_003183
dbSNP: rs200399376
Type: single nucleotide variant
Location: chr2:9510006 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 72.72 · 33 PDB
Residue 439: 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-ala439 (accessed [today's date]).

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