Is DONSON p.Tyr280Cys (c.839A>G) pathogenic?

DONSON p.Tyr280Cys (c.839A>G) is classified Uncertain significance in DONSON (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-29). AlphaMissense: ambiguous (0.4461); Very rare (popmax 0.00669%, eas).

How common is DONSON p.Tyr280Cys (c.839A>G) in the general population?

DONSON p.Tyr280Cys (c.839A>G) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about DONSON p.Tyr280Cys (c.839A>G)?

AlphaMissense predicts ambiguous (score 0.4461) — an in-silico prediction, not a clinical call.

DONSON p.Tyr280Cys

c.839A>G · rs1424530479 · VCV1897090

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4461 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Computational evidence

Protein change
AlphaMissense	0.4461	ambiguous
REVEL	0.513	indeterminate
SaProt	LLR -11.60	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 3.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 10 kb · p 0.95 · regional, not allelic
Overall
CADD	23.9	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 0.00669% East Asian · 3/44,848 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.000744% 12/1,612,770 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,949
Remaining individualsnot grpmax-eligible	0.0016%	62,422
African / African-American	0.00133%	74,974
European (non-Finnish)	0.000594%	168,455

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.Tyr280Cys
Coding: c.839A>G
MANE Select: NM_017613
dbSNP: rs1424530479
Type: single nucleotide variant
Location: chr21:33583613 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.94

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

Similar variants

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
DONSON p.Ala429Glu 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-tyr280cys (accessed [today's date]).

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