Is ADAM33 p.Leu289Pro (c.866T>C) pathogenic?

ADAM33 p.Leu289Pro (c.866T>C) is classified Uncertain significance in ADAM33 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-29). AlphaMissense: likely benign (0.2091); Very rare (popmax 0.00993%, amr).

How common is ADAM33 p.Leu289Pro (c.866T>C) in the general population?

ADAM33 p.Leu289Pro (c.866T>C) is very rare (popmax 0.00993%, amr) (gnomAD).

What do computational predictors say about ADAM33 p.Leu289Pro (c.866T>C)?

AlphaMissense predicts likely benign (score 0.2091) — an in-silico prediction, not a clinical call.

ADAM33 p.Leu289Pro

c.866T>C · rs542392977 · VCV2227369

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2091 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00993%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2091	likely benign
REVEL	0.652	pathogenic-leaning
SaProt	LLR -11.54	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 0.92, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 13 kb · p 0.48 · regional, not allelic
Overall
CADD	25.3	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 0.00993% Admixed American · 5/50,368 alleles

Filtering AF 0.00386% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0025%

Overall 0.00248% 38/1,533,236 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00993%	10,074
African / African-American	0.00684%	14,618
Remaining individualsnot grpmax-eligible	0.00335%	29,888
European (non-Finnish)	0.00218%	45,814
South Asian	0.00119%	83,960

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.Leu289Pro
Coding: c.866T>C
MANE Select: NM_025220
dbSNP: rs542392977
Type: single nucleotide variant
Location: chr20:3673784 (GRCh38)
Gene constraint: LOEUF 1.291 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.33 · 2 PDB
Residue 289: an α-helix; 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-leu289pro (accessed [today's date]).

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