Is MSX2 p.Arg87Trp (c.259C>T) pathogenic?

MSX2 p.Arg87Trp (c.259C>T) is classified Uncertain significance in MSX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-08). AlphaMissense: likely benign (0.1723); Ultra-rare (popmax 0.015%, sas); Associated with Cranium bifidum occultum.

What condition is associated with MSX2 p.Arg87Trp (c.259C>T)?

MSX2 p.Arg87Trp (c.259C>T) is associated with Cranium bifidum occultum (ClinVar).

How common is MSX2 p.Arg87Trp (c.259C>T) in the general population?

MSX2 p.Arg87Trp (c.259C>T) is ultra-rare (popmax 0.015%, sas) (gnomAD).

What do computational predictors say about MSX2 p.Arg87Trp (c.259C>T)?

AlphaMissense predicts likely benign (score 0.1723) — an in-silico prediction, not a clinical call.

MSX2 p.Arg87Trp

c.259C>T · VCV3913943

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1723 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cranium bifidum occultum

Computational evidence

Protein change
AlphaMissense	0.1723	likely benign
REVEL	0.561	indeterminate
SaProt	LLR -8.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.56, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 4,510 bp · p 0.06 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.015% South Asian · 13/86,386 alleles

Filtering AF 0.00887% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00704%

Overall 0.00101% 16/1,577,798 alleles · ultra-rare exomes 15/1,425,572 · genomes 1/152,226 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.015%	6,645
European (non-Finnish)	0.000258%	387,983

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.Arg87Trp
Coding: c.259C>T
MANE Select: NM_002449
Type: single nucleotide variant
Location: chr5:174724918 (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.Glu32Val Uncertain significance ★★ ⚠ same condition
MSX2 p.Gly23Arg Uncertain significance ★★ ⚠ same condition
MSX2 p.Gly27Glu 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-arg87trp (accessed [today's date]).

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