Is ADAM33 p.Pro409Ala (c.1225C>G) pathogenic?

ADAM33 p.Pro409Ala (c.1225C>G) is classified Uncertain significance in ADAM33 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-16). AlphaMissense: likely benign (0.0776); Very rare (popmax 0.00114%, sas).

How common is ADAM33 p.Pro409Ala (c.1225C>G) in the general population?

ADAM33 p.Pro409Ala (c.1225C>G) is very rare (popmax 0.00114%, sas) (gnomAD).

What do computational predictors say about ADAM33 p.Pro409Ala (c.1225C>G)?

AlphaMissense predicts likely benign (score 0.0776) — an in-silico prediction, not a clinical call.

ADAM33 p.Pro409Ala

c.1225C>G · VCV3266084

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0776 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00114%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0776	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -11.19	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP -0.46, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 13 kb · p 0.48 · regional, not allelic
Overall
CADD	23.0	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 0.00114% South Asian · 1/88,044 alleles

Overall 7.02e-05% 1/1,424,100 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: ADAM33
Protein: p.Pro409Ala
Coding: c.1225C>G
MANE Select: NM_025220
Type: single nucleotide variant
Location: chr20:3672807 (GRCh38)
Gene constraint: LOEUF 1.291 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.33 · 2 PDB
Residue 409: the peptidase m12b domain

Full ADAM33 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAM33 p.Ala395Val Likely benign ★★ same type
ADAM33 p.Asn109Ser Benign ★★ same type
ADAM33 p.Gly454= Benign ★★ same type
ADAM33 p.Met590Val Benign ★★ same type
ADAM33 p.Trp515Arg Benign ★★ same type
ADAM33 p.Val499= Benign ★★ same type
ADAM33 p.Ala241Gly Uncertain significance ★ ⚠ same type
ADAM33 p.Ala241Ser Uncertain significance ★ ⚠ 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/adam33-p-pro409ala (accessed [today's date]).

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