Is MSX1 p.Pro284Ser (c.850C>T) pathogenic?

MSX1 p.Pro284Ser (c.850C>T) is classified Uncertain significance in MSX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-14). AlphaMissense: ambiguous (0.4495); Very rare (popmax 0.00187%, nfe); Associated with tooth and nail syndrome.

What condition is associated with MSX1 p.Pro284Ser (c.850C>T)?

MSX1 p.Pro284Ser (c.850C>T) is associated with tooth and nail syndrome (ClinVar).

How common is MSX1 p.Pro284Ser (c.850C>T) in the general population?

MSX1 p.Pro284Ser (c.850C>T) is very rare (popmax 0.00187%, nfe) (gnomAD).

What do computational predictors say about MSX1 p.Pro284Ser (c.850C>T)?

AlphaMissense predicts ambiguous (score 0.4495) — an in-silico prediction, not a clinical call.

MSX1 p.Pro284Ser

c.850C>T · rs771885867 · VCV1503933

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4495 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00187%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

tooth and nail syndrome

Computational evidence

Protein change
AlphaMissense	0.4495	ambiguous
REVEL	0.864	moderately pathogenic-leaning
SaProt	LLR -8.21	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 220 bp · p 0.46 · regional, not allelic
Overall
CADD	24.2	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 0.00187% European (non-Finnish) · 22/1,178,518 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00143% 23/1,608,828 alleles · very rare exomes 21/1,456,746 · genomes 2/152,082 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00187%	53,569
Remaining individualsnot grpmax-eligible	0.00161%	62,236

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.Pro284Ser
Coding: c.850C>T
MANE Select: NM_002448
dbSNP: rs771885867
Type: single nucleotide variant
Location: chr4:4863081 (GRCh38)
Gene constraint: LOEUF 1.289 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.06
Residue 284: a UniProt-annotated variant site (in ectd3)

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

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.Pro153Gln Likely benign ★★ ⚠ 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-pro284ser (accessed [today's date]).

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