Is ADAM22 p.Pro81Ala (c.241C>G) pathogenic?

ADAM22 p.Pro81Ala (c.241C>G) is classified Likely benign in ADAM22 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-01). AlphaMissense: likely benign (0.0606); Ultra-rare (popmax 0.0168%, mid).

How common is ADAM22 p.Pro81Ala (c.241C>G) in the general population?

ADAM22 p.Pro81Ala (c.241C>G) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

What do computational predictors say about ADAM22 p.Pro81Ala (c.241C>G)?

AlphaMissense predicts likely benign (score 0.0606) — an in-silico prediction, not a clinical call.

ADAM22 p.Pro81Ala

c.241C>G · rs780652562 · VCV2657660

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0606 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0606	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -5.08	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 -0.31	GERP 1.9
Regional constraint	o/e 1.02	unconstrained · MANE · 180 kb · p 0.71 · regional, not allelic
Overall
CADD	3.43	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 0.0168% Middle Eastern · 1/5,954 alleles

Filtering AF 0.0131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.0118% 190/1,604,318 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,954
European (non-Finnish)	0.015%	6,677
Remaining individualsnot grpmax-eligible	0.0129%	7,755
East Asian	0.00224%	44,716
South Asian	0.00222%	45,058
Admixed American	0.00169%	59,034
African / African-American	0.00134%	74,744

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.Pro81Ala
Coding: c.241C>G
MANE Select: NM_001324418
dbSNP: rs780652562
Type: single nucleotide variant
Location: chr7:87935181 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.55 (gnomAD)
Structure: AlphaFold pLDDT 73.17 · 10 PDB
Residue 81: a UniProt-annotated variant site (in)

Full ADAM22 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAM22 p.Pro81Arg Benign ★★ same residue
ADAM22 p.Arg513Ser Uncertain significance ★★ ⚠ same type
ADAM22 p.Gly164Arg Uncertain significance ★★ ⚠ same type
ADAM22 p.Pro525Thr Uncertain significance ★★ ⚠ same type
ADAM22 p.Thr713Ser Uncertain significance ★★ ⚠ same type
ADAM22 p.Tyr57Cys Uncertain significance ★★ ⚠ same type
ADAM22 p.Val259Ile Uncertain significance ★★ ⚠ same type
ADAM22 c.1393-3T>C Benign ★★ same type

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-pro81ala (accessed [today's date]).

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