Is ADAM17 p.Ser54= (c.162G>A) pathogenic?

ADAM17 p.Ser54= (c.162G>A) is classified Likely benign in ADAM17 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-15). Very rare (popmax 0.00224%, eas); Associated with inflammatory skin and bowel disease, neonatal, 1.

What condition is associated with ADAM17 p.Ser54= (c.162G>A)?

ADAM17 p.Ser54= (c.162G>A) is associated with inflammatory skin and bowel disease, neonatal, 1 (ClinVar).

How common is ADAM17 p.Ser54= (c.162G>A) in the general population?

ADAM17 p.Ser54= (c.162G>A) is very rare (popmax 0.00224%, eas) (gnomAD).

ADAM17 p.Ser54=

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.162G>A · rs762599369 · VCV1606891

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Conditions

inflammatory skin and bowel disease, neonatal, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.40	donor loss at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP -9	GERP -12
Overall
CADD	10.12	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00224% East Asian · 1/44,642 alleles

Filtering AF 0.000501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.00131% 21/1,608,732 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0204%	4,914
East Asiangrpmax	0.00224%	44,642
Admixed American	0.00169%	59,296
Remaining individualsnot grpmax-eligible	0.00161%	62,264
South Asian	0.00111%	90,248
European (non-Finnish)	0.000934%	107,049

Ashkenazi Jewish 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.Ser54=
Coding: c.162G>A
MANE Select: NM_003183
dbSNP: rs762599369
Type: single nucleotide variant
Location: chr2:9543221 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 72.72 · 33 PDB

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.Ser54Leu Uncertain significance ★★ ⚠ 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-ser54 (accessed [today's date]).

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