Is DONSON p.Ser28Arg (c.82A>C) pathogenic?

DONSON p.Ser28Arg (c.82A>C) is classified Conflicting classifications of pathogenicity in DONSON (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-03-24). AlphaMissense: likely benign (0.2873); Rare (popmax 0.369%, mid); Associated with microcephaly-micromelia syndrome.

What condition is associated with DONSON p.Ser28Arg (c.82A>C)?

DONSON p.Ser28Arg (c.82A>C) is associated with microcephaly-micromelia syndrome, microcephaly, short stature, and limb abnormalities (ClinVar).

How common is DONSON p.Ser28Arg (c.82A>C) in the general population?

DONSON p.Ser28Arg (c.82A>C) is rare (popmax 0.369%, mid) (gnomAD).

What do computational predictors say about DONSON p.Ser28Arg (c.82A>C)?

AlphaMissense predicts likely benign (score 0.2873) — an in-silico prediction, not a clinical call.

DONSON p.Ser28Arg

c.82A>C · rs768071555 · VCV431446

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.2873 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.369%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microcephaly-micromelia syndrome

Computational evidence

Protein change
AlphaMissense	0.2873	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -6.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.17	GERP 2.2, phastCons 0.002
Regional constraint	o/e 1.00	unconstrained · MANE · 10 kb · p 0.95 · regional, not allelic
Overall
CADD	15.19	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 0.369% Middle Eastern · 12/3,256 alleles

Filtering AF 0.213% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.167%

Overall 0.0905% 1,134/1,252,790 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.664%	151
Middle Easterngrpmax	0.369%	271
Admixed American	0.191%	523
Remaining individualsnot grpmax-eligible	0.175%	571
European (non-Finnish)	0.084%	1,190
South Asian	0.0456%	2,195
Finnishnot grpmax-eligible	0.0274%	3,654
African / African-American	0.014%	7,147
East Asian	0.00952%	10,507

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser28Arg
Coding: c.82A>C
MANE Select: NM_017613
dbSNP: rs768071555
Type: single nucleotide variant
Location: chr21:33588560 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.94
Residue 28: the 'disordered' region; a UniProt-annotated variant site (no effect on nuclear localization; complements loss of endogenous donson by rescuing the spontaneous fork stalling observed after donson depletion); a modified residue (phosphoserine)

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

Disease context

microcephaly-micromelia syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: microcephaly, short stature, and limb abnormalities

Similar variants

DONSON p.Ser28Ile Uncertain significance ★ ⚠ same residue
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.Gln101Ter Likely pathogenic ★ same condition
DONSON p.Phe292Leu 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-ser28arg (accessed [today's date]).

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