Is ADAM33 p.Arg607Trp (c.1819C>T) pathogenic?

ADAM33 p.Arg607Trp (c.1819C>T) is classified Uncertain significance in ADAM33 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-19). AlphaMissense: likely benign (0.1312); Ultra-rare (popmax 0.0187%, eas).

How common is ADAM33 p.Arg607Trp (c.1819C>T) in the general population?

ADAM33 p.Arg607Trp (c.1819C>T) is ultra-rare (popmax 0.0187%, eas) (gnomAD).

What do computational predictors say about ADAM33 p.Arg607Trp (c.1819C>T)?

AlphaMissense predicts likely benign (score 0.1312) — an in-silico prediction, not a clinical call.

ADAM33 p.Arg607Trp

c.1819C>T · rs202196209 · VCV2310776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1312 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1312	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -9.83	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 2.4	GERP 0.78, phastCons 0.99
Regional constraint	o/e 1.02	unconstrained · MANE · 13 kb · p 0.48 · regional, not allelic
Overall
CADD	23.1	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 0.0187% East Asian · 8/42,734 alleles

Filtering AF 0.00922% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00678%

Overall 0.00196% 31/1,582,298 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0187%	5,342
Admixed American	0.00901%	11,102
South Asian	0.00458%	21,857
African / African-American	0.0027%	37,084
Remaining individualsnot grpmax-eligible	0.00163%	61,228
European (non-Finnish)	0.000945%	105,797

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.Arg607Trp
Coding: c.1819C>T
MANE Select: NM_025220
dbSNP: rs202196209
Type: single nucleotide variant
Location: chr20:3671667 (GRCh38)
Gene constraint: LOEUF 1.291 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.33 · 2 PDB

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

Similar variants

ADAM33 p.Arg607Gln Uncertain significance ★ ⚠ same residue
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

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-arg607trp (accessed [today's date]).

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