Is DONSON p.Arg452Trp (c.1354C>T) pathogenic?

DONSON p.Arg452Trp (c.1354C>T) is classified Uncertain significance in DONSON (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-03). AlphaMissense: ambiguous (0.4542); Very rare (popmax 0.00169%, amr); Associated with Inborn genetic diseases.

What condition is associated with DONSON p.Arg452Trp (c.1354C>T)?

DONSON p.Arg452Trp (c.1354C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DONSON p.Arg452Trp (c.1354C>T) in the general population?

DONSON p.Arg452Trp (c.1354C>T) is very rare (popmax 0.00169%, amr) (gnomAD).

What do computational predictors say about DONSON p.Arg452Trp (c.1354C>T)?

AlphaMissense predicts ambiguous (score 0.4542) — an in-silico prediction, not a clinical call.

DONSON p.Arg452Trp

c.1354C>T · rs751675539 · VCV1930641

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4542 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4542	ambiguous
REVEL	0.516	indeterminate
SaProt	LLR -13.80	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.65 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 10 kb · p 0.95 · 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 0.00169% Admixed American · 1/59,236 alleles

Filtering AF 0.000544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000429%

Overall 0.000932% 15/1,609,398 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00169%	59,236
Remaining individualsnot grpmax-eligible	0.00161%	62,284
African / African-American	0.00134%	74,704
European (non-Finnish)	0.00102%	98,103

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: DONSON
Protein: p.Arg452Trp
Coding: c.1354C>T
MANE Select: NM_017613
dbSNP: rs751675539
Type: single nucleotide variant
Location: chr21:33579559 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.94
Residue 452: a UniProt-annotated variant site (in missla)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DONSON p.Arg452Gln Uncertain significance ★ ⚠ same residue
DONSON p.Arg452Leu Uncertain significance ★ ⚠ same residue
DONSON p.Arg442Ter Pathogenic ★★ same condition
DONSON p.Gln428Ter Pathogenic/Likely pathogenic ★★ same condition
DONSON p.Ala32Gly Uncertain significance ★★ ⚠ same condition
DONSON p.Ala429Glu Uncertain significance ★★ ⚠ same condition
DONSON p.Arg162Gln Uncertain significance ★★ ⚠ same condition
DONSON p.Arg234His Uncertain significance ★★ ⚠ same condition

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/donson-p-arg452trp (accessed [today's date]).

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