Is ADAM33 p.Arg293Pro (c.878G>C) pathogenic?

ADAM33 p.Arg293Pro (c.878G>C) is classified Uncertain significance in ADAM33 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-13). AlphaMissense: likely benign (0.261); Very rare (popmax 8.75e-05%, nfe).

How common is ADAM33 p.Arg293Pro (c.878G>C) in the general population?

ADAM33 p.Arg293Pro (c.878G>C) is very rare (popmax 8.75e-05%, nfe) (gnomAD).

What do computational predictors say about ADAM33 p.Arg293Pro (c.878G>C)?

AlphaMissense predicts likely benign (score 0.261) — an in-silico prediction, not a clinical call.

ADAM33 p.Arg293Pro

c.878G>C · VCV3828976

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.261 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.75e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.261	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -7.50	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 -0.74	GERP -3.9
Regional constraint	o/e 1.02	unconstrained · MANE · 13 kb · p 0.48 · regional, not allelic
Overall
CADD	20.4	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 8.75e-05% European (non-Finnish) · 1/1,142,846 alleles

Overall 6.54e-05% 1/1,528,358 alleles · very rare exomes 1/1,376,094 · genomes 0/152,264 · joint denominator

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.Arg293Pro
Coding: c.878G>C
MANE Select: NM_025220
Type: single nucleotide variant
Location: chr20:3673772 (GRCh38)
Gene constraint: LOEUF 1.291 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.33 · 2 PDB
Residue 293: 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-arg293pro (accessed [today's date]).

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