Is ADAM17 p.Pro18Leu (c.53C>T) pathogenic?

ADAM17 p.Pro18Leu (c.53C>T) is classified Uncertain significance in ADAM17 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-10). AlphaMissense: likely benign (0.1133); Ultra-rare (popmax 0.0495%, nfe); Associated with inflammatory skin and bowel disease, neonatal, 1.

What condition is associated with ADAM17 p.Pro18Leu (c.53C>T)?

ADAM17 p.Pro18Leu (c.53C>T) is associated with inflammatory skin and bowel disease, neonatal, 1 (ClinVar).

How common is ADAM17 p.Pro18Leu (c.53C>T) in the general population?

ADAM17 p.Pro18Leu (c.53C>T) is ultra-rare (popmax 0.0495%, nfe) (gnomAD).

What do computational predictors say about ADAM17 p.Pro18Leu (c.53C>T)?

AlphaMissense predicts likely benign (score 0.1133) — an in-silico prediction, not a clinical call.

ADAM17 p.Pro18Leu

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.53C>T · rs144458353 · VCV574146

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1133 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inflammatory skin and bowel disease, neonatal, 1

Computational evidence

Protein change
AlphaMissense	0.1133	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -1.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 3.1, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 19 kb · p 0.67 · regional, not allelic
Overall
CADD	17.84	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0495% European (non-Finnish) · 581/1,174,906 alleles

Filtering AF 0.0461% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0448%

Overall 0.0386% 619/1,603,296 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0495%	2,022
Remaining individualsnot grpmax-eligible	0.0436%	2,296
Admixed American	0.00854%	11,712
African / African-American	0.00801%	12,479

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.Pro18Leu
Coding: c.53C>T
MANE Select: NM_003183
dbSNP: rs144458353
Type: single nucleotide variant
Location: chr2:9555553 (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.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-pro18leu (accessed [today's date]).

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