Is DONSON p.Glu539Lys (c.1615G>A) pathogenic?

DONSON p.Glu539Lys (c.1615G>A) is classified Likely benign in DONSON (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0683); Rare (popmax 0.496%, afr).

How common is DONSON p.Glu539Lys (c.1615G>A) in the general population?

DONSON p.Glu539Lys (c.1615G>A) is rare (popmax 0.496%, afr) (gnomAD).

What do computational predictors say about DONSON p.Glu539Lys (c.1615G>A)?

AlphaMissense predicts likely benign (score 0.0683) — an in-silico prediction, not a clinical call.

DONSON p.Glu539Lys

c.1615G>A · rs147521584 · VCV711008

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0683 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.496%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0683	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -4.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.53 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.61	GERP 1.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 10 kb · p 0.95 · regional, not allelic
Overall
CADD	18.99	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 0.496% African / African-American · 372/75,032 alleles

Filtering AF 0.454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.438%

Overall 0.0419% 677/1,613,996 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.496%	202
Middle Eastern	0.462%	216
Admixed American	0.0916%	1,091
Remaining individualsnot grpmax-eligible	0.0848%	1,179
European (non-Finnish)	0.0136%	7,329
South Asian	0.00878%	11,385

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.Glu539Lys
Coding: c.1615G>A
MANE Select: NM_017613
dbSNP: rs147521584
Type: single nucleotide variant
Location: chr21:33578393 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.94
Residue 539: 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.Glu539= Likely benign ★ 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-glu539lys (accessed [today's date]).

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