Is DONSON p.Pro57Leu (c.170C>T) pathogenic?

DONSON p.Pro57Leu (c.170C>T) is classified Uncertain significance in DONSON (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-19). AlphaMissense: ambiguous (0.5388); Very rare (popmax 0.00265%, sas).

How common is DONSON p.Pro57Leu (c.170C>T) in the general population?

DONSON p.Pro57Leu (c.170C>T) is very rare (popmax 0.00265%, sas) (gnomAD).

What do computational predictors say about DONSON p.Pro57Leu (c.170C>T)?

AlphaMissense predicts ambiguous (score 0.5388) — an in-silico prediction, not a clinical call.

DONSON p.Pro57Leu

c.170C>T · VCV3618338

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5388 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00265%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5388	ambiguous
REVEL	0.201	benign-leaning
SaProt	LLR -6.39	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 3.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 10 kb · p 0.95 · regional, not allelic
Overall
CADD	24.0	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 0.00265% South Asian · 1/37,760 alleles

Overall 0.000156% 2/1,278,182 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00265%	37,760
African / African-American	0.00155%	64,554

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.Pro57Leu
Coding: c.170C>T
MANE Select: NM_017613
Type: single nucleotide variant
Location: chr21:33588472 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.94
Residue 57: the 'disordered' region

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-pro57leu (accessed [today's date]).

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