Is DONSON p.Pro224Ser (c.670C>T) pathogenic?

DONSON p.Pro224Ser (c.670C>T) is classified Conflicting classifications of pathogenicity in DONSON (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-09-22). AlphaMissense: likely pathogenic (0.9684); Very rare (popmax 0.00238%, nfe); Associated with microcephaly, short stature, and limb abnormalities.

What condition is associated with DONSON p.Pro224Ser (c.670C>T)?

DONSON p.Pro224Ser (c.670C>T) is associated with microcephaly, short stature, and limb abnormalities, Meier-Gorlin syndrome (ClinVar).

How common is DONSON p.Pro224Ser (c.670C>T) in the general population?

DONSON p.Pro224Ser (c.670C>T) is very rare (popmax 0.00238%, nfe) (gnomAD).

What do computational predictors say about DONSON p.Pro224Ser (c.670C>T)?

AlphaMissense predicts likely pathogenic (score 0.9684) — an in-silico prediction, not a clinical call.

DONSON p.Pro224Ser

c.670C>T · rs1028163227 · VCV1012222

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9684 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00238%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microcephaly, short stature, and limb abnormalities

Computational evidence

Protein change
AlphaMissense	0.9684	likely pathogenic · top 3% in DONSON
REVEL	0.788	moderately pathogenic-leaning
SaProt	LLR -12.72	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 5.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 10 kb · p 0.95 · regional, not allelic
Overall
CADD	25.6	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 0.00238% European (non-Finnish) · 28/1,178,730 alleles

Filtering AF 0.00165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.0018% 29/1,612,190 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00238%	42,097
Remaining individualsnot grpmax-eligible	0.0016%	62,372

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.Pro224Ser
Coding: c.670C>T
MANE Select: NM_017613
dbSNP: rs1028163227
Type: single nucleotide variant
Location: chr21:33584705 (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

microcephaly, short stature, and limb abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Meier-Gorlin syndrome

Similar variants

DONSON c.1047-9A>G Pathogenic ★★ same condition
DONSON c.1563+1G>T Pathogenic ★★ same condition
DONSON p.Gln428Ter Pathogenic/Likely pathogenic ★★ same condition
DONSON p.Phe165Ser Pathogenic/Likely pathogenic ★★ same condition
DONSON p.Ile307Val Uncertain significance ★★ ⚠ same condition
DONSON c.607-36G>A Pathogenic ★ same condition
DONSON p.Arg211Cys Pathogenic ★ ⚠ same condition
DONSON p.Gln101Ter Likely pathogenic ★ 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-pro224ser (accessed [today's date]).

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