Is DONSON p.Lys419Ter (c.1254dup) pathogenic?

DONSON p.Lys419Ter (c.1254dup) is classified Pathogenic/Likely pathogenic in DONSON (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-25). Very rare (popmax 0.00223%, eas); Associated with microcephaly, short stature, and limb abnormalities.

What condition is associated with DONSON p.Lys419Ter (c.1254dup)?

DONSON p.Lys419Ter (c.1254dup) is associated with microcephaly, short stature, and limb abnormalities (ClinVar).

How common is DONSON p.Lys419Ter (c.1254dup) in the general population?

DONSON p.Lys419Ter (c.1254dup) is very rare (popmax 0.00223%, eas) (gnomAD).

DONSON p.Lys419Ter

c.1254dup · rs765112107 · VCV521608

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

microcephaly, short stature, and limb abnormalities

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.2	GERP 5.8, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,886 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000929% 15/1,613,968 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,886
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,088
European (non-Finnish)	0.00102%	98,332

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.Lys419Ter
Coding: c.1254dup
MANE Select: NM_017613
dbSNP: rs765112107
Type: Duplication
Location: chr21:33581397 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.94
Residue 419: a UniProt-annotated variant site (in missla)

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

Disease context

microcephaly, short stature, and limb abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DONSON p.Leu49fs Pathogenic ★ same condition
DONSON c.1047-9A>G Pathogenic ★★ same condition
DONSON c.1563+1G>T Pathogenic ★★ same condition
DONSON p.Gln428Ter Pathogenic/Likely pathogenic ★★ same condition
DONSON p.Phe165Ser Pathogenic/Likely pathogenic ★★ same condition
DONSON p.Ile307Val Uncertain significance ★★ ⚠ same condition
DONSON p.Asn417_Ser418del Likely pathogenic ★ same condition
DONSON p.Gln101Ter Likely pathogenic ★ 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-lys419ter (accessed [today's date]).

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