Is DONSON p.Pro279Leu (c.836C>T) pathogenic?

DONSON p.Pro279Leu (c.836C>T) is classified Uncertain significance in DONSON (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-22). AlphaMissense: ambiguous (0.4265); Rare (popmax 0.129%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DONSON p.Pro279Leu (c.836C>T)?

DONSON p.Pro279Leu (c.836C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DONSON p.Pro279Leu (c.836C>T) in the general population?

DONSON p.Pro279Leu (c.836C>T) is rare (popmax 0.129%, nfe) (gnomAD).

What do computational predictors say about DONSON p.Pro279Leu (c.836C>T)?

AlphaMissense predicts ambiguous (score 0.4265) — an in-silico prediction, not a clinical call.

DONSON p.Pro279Leu

c.836C>T · rs147115711 · VCV1474061

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4265 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.129%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4265	ambiguous
REVEL	0.631	indeterminate
SaProt	LLR -11.66	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.24 · evaluated, not missing
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	28.4	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 0.129% European (non-Finnish) · 1,518/1,178,672 alleles

Filtering AF 0.123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.121%

Overall 0.105% 1,686/1,611,980 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.129%	776
Remaining individualsnot grpmax-eligible	0.0866%	1,155
Finnishnot grpmax-eligible	0.0595%	1,682
South Asian	0.0473%	2,112
Admixed American	0.035%	2,854
Middle Eastern	0.0165%	6,050
African / African-American	0.0147%	6,814

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.Pro279Leu
Coding: c.836C>T
MANE Select: NM_017613
dbSNP: rs147115711
Type: single nucleotide variant
Location: chr21:33583616 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.94

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-pro279leu (accessed [today's date]).

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