Is MSX1 p.Pro153Gln (c.458C>A) pathogenic?

MSX1 p.Pro153Gln (c.458C>A) is classified Likely benign in MSX1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-05-02). AlphaMissense: likely benign (0.2253); Ultra-rare (popmax 0.0625%, eas); Associated with tooth and nail syndrome.

What condition is associated with MSX1 p.Pro153Gln (c.458C>A)?

MSX1 p.Pro153Gln (c.458C>A) is associated with tooth and nail syndrome, orofacial cleft 5 (ClinVar).

How common is MSX1 p.Pro153Gln (c.458C>A) in the general population?

MSX1 p.Pro153Gln (c.458C>A) is ultra-rare (popmax 0.0625%, eas) (gnomAD).

What do computational predictors say about MSX1 p.Pro153Gln (c.458C>A)?

AlphaMissense predicts likely benign (score 0.2253) — an in-silico prediction, not a clinical call.

MSX1 p.Pro153Gln

c.458C>A · rs104893854 · VCV14885

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2253 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0625%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tooth and nail syndrome

Computational evidence

Protein change
AlphaMissense	0.2253	likely benign
REVEL	0.844	moderately pathogenic-leaning
SaProt	LLR -7.28	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 0.51, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 2,960 bp · p 0.0052 · regional, not allelic
Overall
CADD	25.7	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 0.0625% East Asian · 28/44,788 alleles

Filtering AF 0.0444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0383%

Overall 0.00586% 94/1,603,696 alleles · ultra-rare exomes 80/1,451,516 · genomes 14/152,180 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0625%	1,600
South Asian	0.0396%	2,526
Remaining individualsnot grpmax-eligible	0.037%	2,706
African / African-American	0.00534%	18,742
European (non-Finnish)	0.000254%	393,089

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: MSX1
Protein: p.Pro153Gln
Coding: c.458C>A
MANE Select: NM_002448
dbSNP: rs104893854
Type: single nucleotide variant
Location: chr4:4860357 (GRCh38)
Gene constraint: LOEUF 1.289 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.06
Residue 153: the 'disordered' region

Full MSX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

tooth and nail syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: orofacial cleft 5

Similar variants

MSX1 p.Ala182Thr Uncertain significance ★★ ⚠ same condition
MSX1 p.Ala261Gly Uncertain significance ★★ ⚠ same condition
MSX1 p.Arg224Cys Uncertain significance ★★ ⚠ same condition
MSX1 p.Val263Leu Uncertain significance ★★ ⚠ same condition
MSX1 c.*276A>G Benign ★★ same condition
MSX1 c.*6C>T Benign ★★ same condition
MSX1 p.Leu187= Benign/Likely benign ★★ same condition
MSX1 p.Gln221Ter Pathogenic ★ 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/msx1-p-pro153gln (accessed [today's date]).

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