Is DONSON p.Arg553Trp (c.1657C>T) pathogenic?

DONSON p.Arg553Trp (c.1657C>T) is classified Uncertain significance in DONSON (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-02-14). AlphaMissense: likely benign (0.1962); Ultra-rare (popmax 0.0493%, mid); Associated with DONSON-related disorder.

What condition is associated with DONSON p.Arg553Trp (c.1657C>T)?

DONSON p.Arg553Trp (c.1657C>T) is associated with DONSON-related disorder (ClinVar).

How common is DONSON p.Arg553Trp (c.1657C>T) in the general population?

DONSON p.Arg553Trp (c.1657C>T) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about DONSON p.Arg553Trp (c.1657C>T)?

AlphaMissense predicts likely benign (score 0.1962) — an in-silico prediction, not a clinical call.

DONSON p.Arg553Trp

c.1657C>T · rs113553347 · VCV3046432

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1962 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

DONSON-related disorder

Computational evidence

Protein change
AlphaMissense	0.1962	likely benign
REVEL	0.32	indeterminate
SaProt	LLR -12.65	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 2.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 10 kb · p 0.95 · regional, not allelic
Overall
CADD	24.1	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 0.0493% Middle Eastern · 3/6,080 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00716%

Overall 0.00335% 54/1,613,846 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,027
Admixed American	0.00667%	14,999
European (non-Finnish)	0.00373%	26,817
South Asian	0.00329%	30,359

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.Arg553Trp
Coding: c.1657C>T
MANE Select: NM_017613
dbSNP: rs113553347
Type: single nucleotide variant
Location: chr21:33578351 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.94
Residue 553: a UniProt-annotated variant site (in missla)

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

Disease context

DONSON-related disorder

Similar variants

DONSON p.Arg553Gln Uncertain significance ★★ ⚠ same residue
DONSON p.Arg293Ter Pathogenic ★★ same condition
DONSON c.786-7T>C Conflicting classifications of pathogenicity ★ same condition
DONSON p.Lys489Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
DONSON c.1563+1G>A Likely pathogenic same condition
DONSON p.Ala104fs Likely pathogenic ★ same condition
DONSON c.607-31_607-27del Likely benign same condition
DONSON c.1047-9A>G Pathogenic ★★ 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/donson-p-arg553trp (accessed [today's date]).

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