Is ADAM17 p.Pro491Ser (c.1471C>T) pathogenic?

ADAM17 p.Pro491Ser (c.1471C>T) is classified Likely benign in ADAM17 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely pathogenic (0.6883); Rare (popmax 0.258%, amr); Associated with inflammatory skin and bowel disease, neonatal, 1.

What condition is associated with ADAM17 p.Pro491Ser (c.1471C>T)?

ADAM17 p.Pro491Ser (c.1471C>T) is associated with inflammatory skin and bowel disease, neonatal, 1 (ClinVar).

How common is ADAM17 p.Pro491Ser (c.1471C>T) in the general population?

ADAM17 p.Pro491Ser (c.1471C>T) is rare (popmax 0.258%, amr) (gnomAD).

What do computational predictors say about ADAM17 p.Pro491Ser (c.1471C>T)?

AlphaMissense predicts likely pathogenic (score 0.6883) — an in-silico prediction, not a clinical call.

ADAM17 p.Pro491Ser

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.1471C>T · rs55937573 · VCV539947

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6883 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.258%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

inflammatory skin and bowel disease, neonatal, 1

Computational evidence

Protein change
AlphaMissense	0.6883	likely pathogenic
REVEL	0.352	indeterminate
SaProt	LLR -8.78	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 43 kb · p 2.2e-17 · regional, not allelic
Overall
CADD	24.6	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

Grpmax group 0.258% Admixed American · 155/60,002 alleles

Filtering AF 0.225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.213%

Overall 0.0446% 720/1,614,098 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.258%	387
Remaining individualsnot grpmax-eligible	0.107%	933
Middle Eastern	0.0495%	2,021
European (non-Finnish)	0.0401%	2,495
African / African-American	0.016%	6,251
Finnishnot grpmax-eligible	0.0141%	7,114
South Asian	0.0011%	91,074

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.Pro491Ser
Coding: c.1471C>T
MANE Select: NM_003183
dbSNP: rs55937573
Type: single nucleotide variant
Location: chr2:9505239 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 72.72 · 33 PDB
Residue 491: the disintegrin 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-pro491ser (accessed [today's date]).

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