Is ADAM22 p.Lys321Arg (c.962A>G) pathogenic?

ADAM22 p.Lys321Arg (c.962A>G) is classified Uncertain significance in ADAM22 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-31). AlphaMissense: likely benign (0.077); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with ADAM22 p.Lys321Arg (c.962A>G)?

ADAM22 p.Lys321Arg (c.962A>G) is associated with Inborn genetic diseases (ClinVar).

How common is ADAM22 p.Lys321Arg (c.962A>G) in the general population?

ADAM22 p.Lys321Arg (c.962A>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ADAM22 p.Lys321Arg (c.962A>G)?

AlphaMissense predicts likely benign (score 0.077) — an in-silico prediction, not a clinical call.

ADAM22 p.Lys321Arg

c.962A>G · VCV3828450

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.077 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.077	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -5.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 4.8, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 80 kb · p 2.1e-12 · regional, not allelic
Overall
CADD	21.8	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 0.00267% African / African-American · 2/74,906 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00131% 2/152,160 alleles · very rare

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: ADAM22
Protein: p.Lys321Arg
Coding: c.962A>G
MANE Select: NM_001324418
Type: single nucleotide variant
Location: chr7:88131405 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.55 (gnomAD)
Structure: AlphaFold pLDDT 73.17 · 10 PDB
Residue 321: the peptidase m12b domain

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-lys321arg (accessed [today's date]).

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