Is ADAM22 p.Pro22Ala (c.64C>G) pathogenic?

ADAM22 p.Pro22Ala (c.64C>G) is classified Uncertain significance in ADAM22 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-09). AlphaMissense: likely benign (0.0489); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with ADAM22 p.Pro22Ala (c.64C>G)?

ADAM22 p.Pro22Ala (c.64C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ADAM22 p.Pro22Ala (c.64C>G) in the general population?

ADAM22 p.Pro22Ala (c.64C>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ADAM22 p.Pro22Ala (c.64C>G)?

AlphaMissense predicts likely benign (score 0.0489) — an in-silico prediction, not a clinical call.

ADAM22 p.Pro22Ala

c.64C>G · VCV4225936

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0489 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0489	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -5.83	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 0.045	GERP -0.32, phastCons 0.001
Regional constraint	o/e 1.02	unconstrained · MANE · 180 kb · p 0.71 · regional, not allelic
Overall
CADD	2.214	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 0.0011% South Asian · 1/90,714 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000275% 4/1,456,610 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,714
European (non-Finnish)	0.000254%	393,195

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.Pro22Ala
Coding: c.64C>G
MANE Select: NM_001324418
Type: single nucleotide variant
Location: chr7:87934529 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.55 (gnomAD)
Structure: AlphaFold pLDDT 73.17 · 10 PDB

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-pro22ala (accessed [today's date]).

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