Is DONSON p.Pro15Leu (c.44C>T) pathogenic?

DONSON p.Pro15Leu (c.44C>T) is classified Uncertain significance in DONSON (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-22). AlphaMissense: ambiguous (0.3732); Very rare (popmax 0.00407%, amr); Associated with Inborn genetic diseases.

What condition is associated with DONSON p.Pro15Leu (c.44C>T)?

DONSON p.Pro15Leu (c.44C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DONSON p.Pro15Leu (c.44C>T) in the general population?

DONSON p.Pro15Leu (c.44C>T) is very rare (popmax 0.00407%, amr) (gnomAD).

What do computational predictors say about DONSON p.Pro15Leu (c.44C>T)?

AlphaMissense predicts ambiguous (score 0.3732) — an in-silico prediction, not a clinical call.

DONSON p.Pro15Leu

c.44C>T · VCV3842101

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3732 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00407%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3732	ambiguous
REVEL	0.501	indeterminate
SaProt	LLR -6.97	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.9	GERP 3.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 10 kb · p 0.95 · regional, not allelic
Overall
CADD	27.2	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 0.00407% Admixed American · 1/24,544 alleles

Filtering AF 0.00163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.002% 25/1,250,052 alleles · very rare exomes 24/1,098,162 · genomes 1/151,890 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00407%	24,544
European (non-Finnish)	0.00241%	41,504

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.Pro15Leu
Coding: c.44C>T
MANE Select: NM_017613
Type: single nucleotide variant
Location: chr21:33588598 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.94
Residue 15: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DONSON p.Arg442Ter Pathogenic ★★ same condition
DONSON p.Gln428Ter Pathogenic/Likely pathogenic ★★ same condition
DONSON p.Ala32Gly Uncertain significance ★★ ⚠ same condition
DONSON p.Ala429Glu Uncertain significance ★★ ⚠ same condition
DONSON p.Arg162Gln Uncertain significance ★★ ⚠ same condition
DONSON p.Arg234His Uncertain significance ★★ ⚠ same condition
DONSON p.Arg239Ser Uncertain significance ★★ ⚠ same condition
DONSON p.Arg29Cys Uncertain significance ★★ ⚠ 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-pro15leu (accessed [today's date]).

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