Is MSX2 p.Pro148Ser (c.442C>T) pathogenic?

MSX2 p.Pro148Ser (c.442C>T) is classified Uncertain significance in MSX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-06). AlphaMissense: likely pathogenic (0.9975); Absent from gnomAD v4.1; Associated with Cranium bifidum occultum.

What condition is associated with MSX2 p.Pro148Ser (c.442C>T)?

MSX2 p.Pro148Ser (c.442C>T) is associated with Cranium bifidum occultum (ClinVar).

How common is MSX2 p.Pro148Ser (c.442C>T) in the general population?

MSX2 p.Pro148Ser (c.442C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MSX2 p.Pro148Ser (c.442C>T)?

AlphaMissense predicts likely pathogenic (score 0.9975) — an in-silico prediction, not a clinical call.

MSX2 p.Pro148Ser

c.442C>T · rs1581520079 · VCV639933

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9975 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cranium bifidum occultum

Computational evidence

Protein change
AlphaMissense	0.9975	likely pathogenic
REVEL	0.685	pathogenic-leaning
SaProt	LLR -13.94	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 409 bp · p 0.00015 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MSX2
Protein: p.Pro148Ser
Coding: c.442C>T
MANE Select: NM_002449
dbSNP: rs1581520079
Type: single nucleotide variant
Location: chr5:174729221 (GRCh38)
Gene constraint: LOEUF 1.013 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 68.77
Residue 148: a DNA-binding region; a UniProt-annotated variant site (in crs2; gain of function); a UniProt-annotated variant site (in crs2)

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.Pro148Leu Pathogenic ★ same residue
MSX2 p.Pro148= Benign ★ same residue
MSX2 p.Pro148His Pathogenic ★★ 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

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-pro148ser (accessed [today's date]).

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