Is DONSON p.Asp251Gly (c.752A>G) pathogenic?

DONSON p.Asp251Gly (c.752A>G) is classified Conflicting classifications of pathogenicity in DONSON (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-23). AlphaMissense: likely pathogenic (0.7095); Rare (popmax 0.938%, sas).

How common is DONSON p.Asp251Gly (c.752A>G) in the general population?

DONSON p.Asp251Gly (c.752A>G) is rare (popmax 0.938%, sas) (gnomAD).

What do computational predictors say about DONSON p.Asp251Gly (c.752A>G)?

AlphaMissense predicts likely pathogenic (score 0.7095) — an in-silico prediction, not a clinical call.

DONSON p.Asp251Gly

c.752A>G · rs61746119 · VCV1630560

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7095 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.938%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7095	likely pathogenic
REVEL	0.476	indeterminate
SaProt	LLR -11.04	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 4.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 10 kb · p 0.95 · regional, not allelic
Overall
CADD	26.5	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 0.938% South Asian · 853/90,940 alleles

Filtering AF 0.886% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.865%

Overall 0.0772% 1,246/1,613,144 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.938%	107
Middle Eastern	0.264%	379
Ashkenazi Jewishnot grpmax-eligible	0.193%	519
Remaining individualsnot grpmax-eligible	0.12%	833
European (non-Finnish)	0.0199%	5,018
Admixed American	0.015%	6,660
African / African-American	0.00133%	75,026

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.Asp251Gly
Coding: c.752A>G
MANE Select: NM_017613
dbSNP: rs61746119
Type: single nucleotide variant
Location: chr21:33584623 (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

Similar variants

DONSON p.Asp251Asn Uncertain significance ★★ ⚠ 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-asp251gly (accessed [today's date]).

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