Is MSX2 p.Ser218Phe (c.653C>T) pathogenic?

MSX2 p.Ser218Phe (c.653C>T) is classified Uncertain significance in MSX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). AlphaMissense: ambiguous (0.3499); Very rare (popmax 0.00167%, amr); Associated with Cranium bifidum occultum.

What condition is associated with MSX2 p.Ser218Phe (c.653C>T)?

MSX2 p.Ser218Phe (c.653C>T) is associated with Cranium bifidum occultum (ClinVar).

How common is MSX2 p.Ser218Phe (c.653C>T) in the general population?

MSX2 p.Ser218Phe (c.653C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about MSX2 p.Ser218Phe (c.653C>T)?

AlphaMissense predicts ambiguous (score 0.3499) — an in-silico prediction, not a clinical call.

MSX2 p.Ser218Phe

c.653C>T · rs760162567 · VCV2787587

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3499 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

Cranium bifidum occultum

Computational evidence

Protein change
AlphaMissense	0.3499	ambiguous
REVEL	0.464	indeterminate
SaProt	LLR -9.82	tolerated
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	25.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,006 alleles

Overall 0.000124% 2/1,614,010 alleles · very rare exomes 1/1,461,768 · genomes 1/152,242 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,006
South Asian	0.0011%	91,086

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.Ser218Phe
Coding: c.653C>T
MANE Select: NM_002449
dbSNP: rs760162567
Type: single nucleotide variant
Location: chr5:174729432 (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.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-ser218phe (accessed [today's date]).

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