Is DONSON p.Ser28Ile (c.83G>T) pathogenic?

DONSON p.Ser28Ile (c.83G>T) is classified Uncertain significance in DONSON (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-10). AlphaMissense: likely benign (0.1956); Very rare (popmax 0.00778%, afr).

How common is DONSON p.Ser28Ile (c.83G>T) in the general population?

DONSON p.Ser28Ile (c.83G>T) is very rare (popmax 0.00778%, afr) (gnomAD).

What do computational predictors say about DONSON p.Ser28Ile (c.83G>T)?

AlphaMissense predicts likely benign (score 0.1956) — an in-silico prediction, not a clinical call.

DONSON p.Ser28Ile

c.83G>T · rs1273970185 · VCV1965930

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1956 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00778%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1956	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -9.68	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 -1.1	GERP 2.5
Regional constraint	o/e 1.00	unconstrained · MANE · 10 kb · p 0.95 · regional, not allelic
Overall
CADD	16.18	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00778% African / African-American · 5/64,278 alleles

Filtering AF 0.00297% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000479% 6/1,252,728 alleles · very rare exomes 2/1,100,860 · genomes 4/151,868 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00778%	12,856
Admixed American	0.00416%	24,024

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.Ser28Ile
Coding: c.83G>T
MANE Select: NM_017613
dbSNP: rs1273970185
Type: single nucleotide variant
Location: chr21:33588559 (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

Similar variants

DONSON p.Ser28Arg 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-ser28ile (accessed [today's date]).

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