Is MSX2 p.Arg39= (c.117C>T) pathogenic?

MSX2 p.Arg39= (c.117C>T) is classified Benign in MSX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-20). Rare (popmax 0.315%, afr); Associated with Cranium bifidum occultum.

What condition is associated with MSX2 p.Arg39= (c.117C>T)?

MSX2 p.Arg39= (c.117C>T) is associated with Cranium bifidum occultum (ClinVar).

How common is MSX2 p.Arg39= (c.117C>T) in the general population?

MSX2 p.Arg39= (c.117C>T) is rare (popmax 0.315%, afr) (gnomAD).

MSX2 p.Arg39=

c.117C>T · rs376630472 · VCV1651356

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.315%, afr)

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 1.6	GERP -0.43, phastCons 1
Overall
CADD	14.15	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.315% African / African-American · 232/73,624 alleles

Filtering AF 0.282% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.269%

Overall 0.0164% 255/1,557,378 alleles · rare exomes 120/1,405,048 · genomes 135/152,330 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.315%	317
Remaining individualsnot grpmax-eligible	0.0182%	5,481
Admixed American	0.0155%	6,452
South Asian	0.00118%	84,908
European (non-Finnish)	0.000261%	383,758

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.Arg39=
Coding: c.117C>T
MANE Select: NM_002449
dbSNP: rs376630472
Type: single nucleotide variant
Location: chr5:174724776 (GRCh38)
Gene constraint: LOEUF 1.013 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 68.77
Residue 39: the 'disordered' region

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.Arg39Leu Uncertain significance ★★ ⚠ same residue
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.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-arg39 (accessed [today's date]).

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