Is MSX2 p.Thr101= (c.303C>T) pathogenic?

MSX2 p.Thr101= (c.303C>T) is classified Likely benign in MSX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-25). Very rare (popmax 0.00225%, eas); Associated with Cranium bifidum occultum.

What condition is associated with MSX2 p.Thr101= (c.303C>T)?

MSX2 p.Thr101= (c.303C>T) is associated with Cranium bifidum occultum (ClinVar).

How common is MSX2 p.Thr101= (c.303C>T) in the general population?

MSX2 p.Thr101= (c.303C>T) is very rare (popmax 0.00225%, eas) (gnomAD).

MSX2 p.Thr101=

c.303C>T · VCV4744389

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00225%, 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 -2.2	GERP -3
Overall
CADD	4.722	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00225% East Asian · 1/44,454 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000482% 7/1,450,842 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00225%	44,454
European (non-Finnish)	0.00051%	196,127

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.Thr101=
Coding: c.303C>T
MANE Select: NM_002449
Type: single nucleotide variant
Location: chr5:174724962 (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

Similar variants

MSX2 p.Gln153Ter Pathogenic/Likely 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
MSX2 p.Gly23Arg 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-thr101 (accessed [today's date]).

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