Is DONSON p.Ser497fs (c.1487dup) pathogenic?

DONSON p.Ser497fs (c.1487dup) is classified Pathogenic in DONSON (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-07). Very rare (popmax 0.00167%, amr).

How common is DONSON p.Ser497fs (c.1487dup) in the general population?

DONSON p.Ser497fs (c.1487dup) is very rare (popmax 0.00167%, amr) (gnomAD).

DONSON p.Ser497fs

c.1487dup · rs1450835871 · VCV2098376

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1	GERP 0.78, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,016 alleles

Overall 6.84e-05% 1/1,461,840 alleles · very rare

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.Ser497fs
Coding: c.1487dup
MANE Select: NM_017613
dbSNP: rs1450835871
Type: Duplication
Location: chr21:33579425 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.94
Residue 497: a UniProt-annotated variant site (in missla)

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

Similar variants

DONSON p.Lys419Ter Pathogenic/Likely pathogenic ★★ same type
DONSON p.Ile382fs Pathogenic ★ same type
DONSON p.Leu49fs Pathogenic ★ same type
DONSON p.Pro15fs Pathogenic ★ same type
DONSON p.Ser363fs Pathogenic ★ same type
DONSON c.1047-20dup Likely benign ★ 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-ser497fs (accessed [today's date]).

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