Is MSX2 p.Ala197= (c.591G>A) pathogenic?

MSX2 p.Ala197= (c.591G>A) is classified Likely benign in MSX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-16). Very rare (popmax 0.00668%, eas); Associated with Cranium bifidum occultum.

What condition is associated with MSX2 p.Ala197= (c.591G>A)?

MSX2 p.Ala197= (c.591G>A) is associated with Cranium bifidum occultum (ClinVar).

How common is MSX2 p.Ala197= (c.591G>A) in the general population?

MSX2 p.Ala197= (c.591G>A) is very rare (popmax 0.00668%, eas) (gnomAD).

MSX2 p.Ala197=

c.591G>A · rs150352201 · VCV2716797

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00668%, 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 -3.1	GERP -4.2
Overall
CADD	6.981	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% East Asian · 3/44,888 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00211% 34/1,614,034 alleles · very rare exomes 29/1,461,888 · genomes 5/152,146 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,963
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	0.00229%	43,705
South Asian	0.0011%	91,084

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.Ala197=
Coding: c.591G>A
MANE Select: NM_002449
dbSNP: rs150352201
Type: single nucleotide variant
Location: chr5:174729370 (GRCh38)
Gene constraint: LOEUF 1.013 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 68.77
Residue 197: a DNA-binding 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.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-ala197 (accessed [today's date]).

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