Is ADAM17 p.Ser504Arg (c.1512C>G) pathogenic?

ADAM17 p.Ser504Arg (c.1512C>G) is classified Uncertain significance in ADAM17 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-17). AlphaMissense: likely benign (0.1238); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ADAM17 p.Ser504Arg (c.1512C>G)?

ADAM17 p.Ser504Arg (c.1512C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ADAM17 p.Ser504Arg (c.1512C>G) in the general population?

ADAM17 p.Ser504Arg (c.1512C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ADAM17 p.Ser504Arg (c.1512C>G)?

AlphaMissense predicts likely benign (score 0.1238) — an in-silico prediction, not a clinical call.

ADAM17 p.Ser504Arg

c.1512C>G · rs1473249918 · VCV2326232

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1238 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1238	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -4.94	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 -4	GERP -4.2
Regional constraint	o/e 0.67	unconstrained · MANE · 43 kb · p 2.2e-17 · regional, not allelic
Overall
CADD	0.188	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ADAM17
Protein: p.Ser504Arg
Coding: c.1512C>G
MANE Select: NM_003183
dbSNP: rs1473249918
Type: single nucleotide variant
Location: chr2:9505198 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 72.72 · 33 PDB
Residue 504: the disintegrin domain

Full ADAM17 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ADAM17 p.Ser504Gly Uncertain significance ★★ ⚠ same residue
ADAM17 p.Ser504= Likely benign ★★ same residue
ADAM17 p.Ser504Asn Uncertain significance ★ ⚠ same residue
ADAM17 p.Ala806Pro Uncertain significance ★★ ⚠ same condition
ADAM17 p.Ala806Ser Uncertain significance ★★ ⚠ same condition
ADAM17 p.Arg132Lys Uncertain significance ★★ ⚠ same condition
ADAM17 p.Arg813His Uncertain significance ★★ ⚠ same condition
ADAM17 p.Arg816His 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-ser504arg (accessed [today's date]).

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