Is ADAM22 p.Cys554Arg (c.1660T>C) pathogenic?

ADAM22 p.Cys554Arg (c.1660T>C) is classified Uncertain significance in ADAM22 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-09). AlphaMissense: likely pathogenic (0.9992); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ADAM22 p.Cys554Arg (c.1660T>C)?

ADAM22 p.Cys554Arg (c.1660T>C) is associated with Inborn genetic diseases (ClinVar).

How common is ADAM22 p.Cys554Arg (c.1660T>C) in the general population?

ADAM22 p.Cys554Arg (c.1660T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ADAM22 p.Cys554Arg (c.1660T>C)?

AlphaMissense predicts likely pathogenic (score 0.9992) — an in-silico prediction, not a clinical call.

ADAM22 p.Cys554Arg

c.1660T>C · VCV4004924

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9992 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9992	likely pathogenic · top 1% in ADAM22
REVEL	0.643	indeterminate
SaProt	LLR -17.07	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 5.7, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 80 kb · p 2.1e-12 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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: ADAM22
Protein: p.Cys554Arg
Coding: c.1660T>C
MANE Select: NM_001324418
Type: single nucleotide variant
Location: chr7:88151299 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.55 (gnomAD)
Structure: AlphaFold pLDDT 73.17 · 10 PDB
Residue 554: a disulfide bond; an α-helix

Full ADAM22 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

ADAM22 p.Arg513Ser Uncertain significance ★★ ⚠ same condition
ADAM22 p.Gly164Arg Uncertain significance ★★ ⚠ same condition
ADAM22 p.Pro525Thr Uncertain significance ★★ ⚠ same condition
ADAM22 p.Thr713Ser Uncertain significance ★★ ⚠ same condition
ADAM22 p.Tyr57Cys Uncertain significance ★★ ⚠ same condition
ADAM22 p.Val259Ile Uncertain significance ★★ ⚠ same condition
ADAM22 p.Ala524= Likely benign ★★ same condition
ADAM22 c.1617+3A>G 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/adam22-p-cys554arg (accessed [today's date]).

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