Is MSX2 p.Ala233= (c.699G>A) pathogenic?

MSX2 p.Ala233= (c.699G>A) is classified Benign in MSX2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-08). Rare (popmax 0.319%, eas); Associated with Cranium bifidum occultum.

What condition is associated with MSX2 p.Ala233= (c.699G>A)?

MSX2 p.Ala233= (c.699G>A) is associated with Cranium bifidum occultum, parietal foramina 1, craniosynostosis 2 (ClinVar).

How common is MSX2 p.Ala233= (c.699G>A) in the general population?

MSX2 p.Ala233= (c.699G>A) is rare (popmax 0.319%, eas) (gnomAD).

MSX2 p.Ala233=

c.699G>A · rs201880865 · VCV352838

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.319%, eas)

Conditions

Cranium bifidum occultum

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -4.2
Overall
CADD	0.453	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.319% East Asian · 143/44,884 alleles

Filtering AF 0.276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.26%

Overall 0.0122% 197/1,613,896 alleles · rare exomes 176/1,461,654 · genomes 21/152,242 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.319%	314
Middle Eastern	0.033%	3,027
Remaining individualsnot grpmax-eligible	0.0224%	4,464
South Asian	0.0121%	8,279
African / African-American	0.00667%	15,001
European (non-Finnish)	0.00178%	56,185
Admixed American	0.00167%	59,996

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.Ala233=
Coding: c.699G>A
MANE Select: NM_002449
dbSNP: rs201880865
Type: single nucleotide variant
Location: chr5:174729478 (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.Ala233Val Uncertain significance ★ ⚠ same residue
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

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-ala233 (accessed [today's date]).

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