Is MSX2 p.Pro66Arg (c.197C>G) pathogenic?

MSX2 p.Pro66Arg (c.197C>G) is classified Uncertain significance in MSX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-23). AlphaMissense: likely benign (0.0822); Ultra-rare (popmax 0.0448%, afr); Associated with Cranium bifidum occultum.

What condition is associated with MSX2 p.Pro66Arg (c.197C>G)?

MSX2 p.Pro66Arg (c.197C>G) is associated with Cranium bifidum occultum (ClinVar).

How common is MSX2 p.Pro66Arg (c.197C>G) in the general population?

MSX2 p.Pro66Arg (c.197C>G) is ultra-rare (popmax 0.0448%, afr) (gnomAD).

What do computational predictors say about MSX2 p.Pro66Arg (c.197C>G)?

AlphaMissense predicts likely benign (score 0.0822) — an in-silico prediction, not a clinical call.

MSX2 p.Pro66Arg

c.197C>G · rs527786984 · VCV2889152

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0822 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0448%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cranium bifidum occultum

Computational evidence

Protein change
AlphaMissense	0.0822	likely benign
REVEL	0.098	moderately benign-leaning
SaProt	LLR -6.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 1.5, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 4,510 bp · p 0.06 · regional, not allelic
Overall
CADD	21.2	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 0.0448% African / African-American · 33/73,588 alleles

Filtering AF 0.0327% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0286%

Overall 0.0027% 42/1,552,840 alleles · ultra-rare exomes 19/1,400,536 · genomes 23/152,304 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0448%	2,230
Admixed American	0.00588%	16,995
Remaining individualsnot grpmax-eligible	0.00166%	60,130
European (non-Finnish)	0.000435%	229,722

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.Pro66Arg
Coding: c.197C>G
MANE Select: NM_002449
dbSNP: rs527786984
Type: single nucleotide variant
Location: chr5:174724856 (GRCh38)
Gene constraint: LOEUF 1.013 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 68.77
Residue 66: 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.Pro66Leu 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.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-pro66arg (accessed [today's date]).

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