Is DONSON p.Lys489Arg (c.1466A>G) pathogenic?

DONSON p.Lys489Arg (c.1466A>G) is classified Benign/Likely benign in DONSON (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-10). AlphaMissense: likely benign (0.0654); Low-frequency (popmax 1.24%, eas).

How common is DONSON p.Lys489Arg (c.1466A>G) in the general population?

DONSON p.Lys489Arg (c.1466A>G) is low-frequency (popmax 1.24%, eas) (gnomAD).

What do computational predictors say about DONSON p.Lys489Arg (c.1466A>G)?

AlphaMissense predicts likely benign (score 0.0654) — an in-silico prediction, not a clinical call.

DONSON p.Lys489Arg

c.1466A>G · rs146664036 · VCV737509

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0654 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.24%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0654	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -4.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.42	acceptor loss · deltas
Constraint at this position
Conservation	phyloP -7.6	GERP -12
Regional constraint	o/e 1.00	unconstrained · MANE · 10 kb · p 0.95 · regional, not allelic
Overall
CADD	0.002	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 1.24% East Asian · 558/44,878 alleles

Filtering AF 1.16% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.12%

Overall 0.0362% 585/1,614,182 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1.24%	80
Remaining individualsnot grpmax-eligible	0.0336%	2,977
South Asian	0.0022%	45,542
European (non-Finnish)	0.000339%	295,005

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.Lys489Arg
Coding: c.1466A>G
MANE Select: NM_017613
dbSNP: rs146664036
Type: single nucleotide variant
Location: chr21:33579447 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.94
Residue 489: a UniProt-annotated variant site (in missla); a UniProt-annotated variant site (in missla; uncertain significance; reduced protein level; no effect on nuclear localization; does not complement loss of endogenous donson when tested for the rescue of the spontaneous fork stalling observed after donson depletion)

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

Similar variants

DONSON p.Lys489Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
DONSON c.1047-9A>G Pathogenic ★★ same type
DONSON c.1563+1G>T Pathogenic ★★ same type
DONSON p.Arg293Ter Pathogenic ★★ same type
DONSON p.Arg442Ter Pathogenic ★★ same type
DONSON p.Gln428Ter Pathogenic/Likely pathogenic ★★ same type
DONSON p.Phe165Ser Pathogenic/Likely pathogenic ★★ same type
DONSON p.Ala32Gly 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/donson-p-lys489arg (accessed [today's date]).

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