Is DONSON p.Pro478Leu (c.1433C>T) pathogenic?

DONSON p.Pro478Leu (c.1433C>T) is classified Pathogenic in DONSON (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-03). AlphaMissense: likely pathogenic (0.84); Very rare (popmax 0.00167%, amr).

How common is DONSON p.Pro478Leu (c.1433C>T) in the general population?

DONSON p.Pro478Leu (c.1433C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about DONSON p.Pro478Leu (c.1433C>T)?

AlphaMissense predicts likely pathogenic (score 0.84) — an in-silico prediction, not a clinical call.

DONSON p.Pro478Leu

c.1433C>T · rs372126686 · VCV1410377

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.84 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.84	likely pathogenic ✓ concordant with ClinVar
REVEL	0.729	pathogenic-leaning
SaProt	LLR -13.40	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 5.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 10 kb · p 0.95 · regional, not allelic
Overall
CADD	25.9	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 0.00167% Admixed American · 1/60,010 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.000991% 16/1,614,106 alleles · very rare exomes 14/1,461,866 · genomes 2/152,240 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,010
European (non-Finnish)	0.00127%	78,670

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.Pro478Leu
Coding: c.1433C>T
MANE Select: NM_017613
dbSNP: rs372126686
Type: single nucleotide variant
Location: chr21:33579480 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.94
Residue 478: a UniProt-annotated variant site (in missla)

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

Similar variants

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
DONSON p.Ala429Glu 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-pro478leu (accessed [today's date]).

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