Is MSX2 p.Pro251Ser (c.751C>T) pathogenic?

MSX2 p.Pro251Ser (c.751C>T) is classified Uncertain significance in MSX2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-30). AlphaMissense: likely benign (0.105); Very rare (popmax 0.005%, amr); Associated with Cranium bifidum occultum.

What condition is associated with MSX2 p.Pro251Ser (c.751C>T)?

MSX2 p.Pro251Ser (c.751C>T) is associated with Cranium bifidum occultum, parietal foramina 1, craniosynostosis 2 (ClinVar).

How common is MSX2 p.Pro251Ser (c.751C>T) in the general population?

MSX2 p.Pro251Ser (c.751C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about MSX2 p.Pro251Ser (c.751C>T)?

AlphaMissense predicts likely benign (score 0.105) — an in-silico prediction, not a clinical call.

MSX2 p.Pro251Ser

c.751C>T · rs776218196 · VCV907440

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.105 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cranium bifidum occultum

Computational evidence

Protein change
AlphaMissense	0.105	likely benign
REVEL	0.678	pathogenic-leaning
SaProt	LLR -7.59	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 409 bp · p 0.00015 · regional, not allelic
Overall
CADD	26.2	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 0.005% Admixed American · 3/59,998 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000992% 16/1,613,616 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,999
African / African-American	0.00133%	74,930
European (non-Finnish)	0.00102%	98,324

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: MSX2
Protein: p.Pro251Ser
Coding: c.751C>T
MANE Select: NM_002449
dbSNP: rs776218196
Type: single nucleotide variant
Location: chr5:174729530 (GRCh38)
Gene constraint: LOEUF 1.013 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 68.77

Full MSX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cranium bifidum occultum — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: parietal foramina 1 craniosynostosis 2

Similar variants

MSX2 p.Gln153Ter Pathogenic/Likely pathogenic ★★ same condition
MSX2 p.Pro148His Pathogenic ★★ same condition
MSX2 p.Ala212Gly Uncertain significance ★★ ⚠ same condition
MSX2 p.Ala238Thr Uncertain significance ★★ ⚠ same condition
MSX2 p.Arg143Gln Uncertain significance ★★ ⚠ same condition
MSX2 p.Arg39Leu Uncertain significance ★★ ⚠ same condition
MSX2 p.Arg87Trp Uncertain significance ★★ ⚠ same condition
MSX2 p.Glu32Val 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/msx2-p-pro251ser (accessed [today's date]).

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