Is MSX2 p.Met1Val (c.1A>G) pathogenic?

MSX2 p.Met1Val (c.1A>G) is classified Likely pathogenic in MSX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-04). Very rare (popmax 0.00135%, afr).

How common is MSX2 p.Met1Val (c.1A>G) in the general population?

MSX2 p.Met1Val (c.1A>G) is very rare (popmax 0.00135%, afr) (gnomAD).

MSX2 p.Met1Val

c.1A>G · rs1349485235 · VCV2442667

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.484	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00135% African / African-American · 1/73,920 alleles

Overall 6.33e-05% 1/1,580,966 alleles · very rare exomes 0/1,430,468 · genomes 1/150,498 · joint denominator

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.Met1Val
Coding: c.1A>G
MANE Select: NM_002449
dbSNP: rs1349485235
Type: single nucleotide variant
Location: chr5:174724660 (GRCh38)
Gene constraint: LOEUF 1.013 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 68.77
Residue 1: the 'disordered' region

Full MSX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MSX2 p.Met1Thr Uncertain significance ★ same residue
MSX2 p.Gln153Ter Pathogenic/Likely pathogenic ★★ same type
MSX2 p.Pro148His Pathogenic ★★ same type
MSX2 p.Ala212Gly Uncertain significance ★★ ⚠ same type
MSX2 p.Ala232Val Uncertain significance ★★ ⚠ same type
MSX2 p.Ala238Thr Uncertain significance ★★ ⚠ same type
MSX2 p.Ala35Pro Uncertain significance ★★ ⚠ same type
MSX2 p.Arg143Gln Uncertain significance ★★ ⚠ same type

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-met1val (accessed [today's date]).

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