Is ADAM17 p.Ser608= (c.1824T>C) pathogenic?

ADAM17 p.Ser608= (c.1824T>C) is classified Benign/Likely benign in ADAM17 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 71.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with inflammatory skin and bowel disease, neonatal, 1.

What condition is associated with ADAM17 p.Ser608= (c.1824T>C)?

ADAM17 p.Ser608= (c.1824T>C) is associated with inflammatory skin and bowel disease, neonatal, 1 (ClinVar).

ADAM17 p.Ser608=

Q: How common is ADAM17 p.Ser608= (c.1824T>C) in the general population?

ADAM17 p.Ser608= (c.1824T>C) is common (popmax 71.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.1824T>C · rs1048610 · VCV1169868

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 71.8%, afr) — too common for a highly-penetrant pathogenic allele

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4	GERP -4.4
Overall
CADD	1.908	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 71.8% African / African-American · 53,790/74,942 alleles

Filtering AF 71.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 71.1%

Overall 56.7% 914,996/1,613,660 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	72.9%	1
African / African-Americangrpmax	71.8%	1
Middle Eastern	67%	1
Ashkenazi Jewishnot grpmax-eligible	63.2%	2
European (non-Finnish)	59.8%	2
Remaining individualsnot grpmax-eligible	57.3%	2
Finnishnot grpmax-eligible	48.4%	2
South Asian	45.9%	2
Admixed American	34.9%	3
East Asian	6.74%	15

Amish 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.Ser608=
Coding: c.1824T>C
MANE Select: NM_003183
dbSNP: rs1048610
Type: single nucleotide variant
Location: chr2:9494727 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 72.72 · 33 PDB
Residue 608: a β-strand; the 'crambin-like' region

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-ser608 (accessed [today's date]).

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