Is MSX2 p.Pro225Arg (c.674C>G) pathogenic?

MSX2 p.Pro225Arg (c.674C>G) is classified Uncertain significance in MSX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-29). AlphaMissense: ambiguous (0.4784); Very rare (popmax 0.00017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MSX2 p.Pro225Arg (c.674C>G)?

MSX2 p.Pro225Arg (c.674C>G) is associated with Inborn genetic diseases (ClinVar).

How common is MSX2 p.Pro225Arg (c.674C>G) in the general population?

MSX2 p.Pro225Arg (c.674C>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about MSX2 p.Pro225Arg (c.674C>G)?

AlphaMissense predicts ambiguous (score 0.4784) — an in-silico prediction, not a clinical call.

MSX2 p.Pro225Arg

c.674C>G · rs1392988082 · VCV2230157

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4784 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4784	ambiguous
REVEL	0.65	pathogenic-leaning
SaProt	LLR -12.33	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 409 bp · p 0.00015 · regional, not allelic
Overall
CADD	29.4	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 0.00017% European (non-Finnish) · 2/1,179,898 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,700 alleles · very rare

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.Pro225Arg
Coding: c.674C>G
MANE Select: NM_002449
dbSNP: rs1392988082
Type: single nucleotide variant
Location: chr5:174729453 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MSX2 p.Pro225Ser Uncertain significance ★ ⚠ same residue
MSX2 p.Ala35Pro Uncertain significance ★★ ⚠ same condition
MSX2 p.Arg159His Uncertain significance ★★ ⚠ same condition
MSX2 p.Gly25Arg Uncertain significance ★★ ⚠ same condition
MSX2 p.His90Gln Uncertain significance ★★ ⚠ same condition
MSX2 p.Met263Ile Uncertain significance ★★ ⚠ same condition
MSX2 p.Ser106Pro Uncertain significance ★★ ⚠ same condition
MSX2 p.Arg162His 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-pro225arg (accessed [today's date]).

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