Is ARX p.Met1Arg (c.2T>G) pathogenic?

ARX p.Met1Arg (c.2T>G) is classified Pathogenic in ARX (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). Very rare (popmax 0.00102%, nfe); Associated with corpus callosum agenesis-abnormal genitalia syndrome.

What condition is associated with ARX p.Met1Arg (c.2T>G)?

ARX p.Met1Arg (c.2T>G) is associated with corpus callosum agenesis-abnormal genitalia syndrome (ClinVar).

How common is ARX p.Met1Arg (c.2T>G) in the general population?

ARX p.Met1Arg (c.2T>G) is very rare (popmax 0.00102%, nfe) (gnomAD).

ARX p.Met1Arg

c.2T>G · rs2147325502 · VCV1685549

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Conditions

corpus callosum agenesis-abnormal genitalia syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function in a haploinsufficient gene (ClinGen)
REVEL	0.856	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Overall
CADD	23.8	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 0.00102% European (non-Finnish) · 9/884,914 alleles

Filtering AF 0.000478% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000347%

Overall 0.000833% 9/1,079,950 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: ARX
Protein: p.Met1Arg
Coding: c.2T>G
MANE Select: NM_139058
dbSNP: rs2147325502
Type: single nucleotide variant
Location: chrX:25015736 (GRCh38)
Structure: AlphaFold pLDDT 56.51
Residue 1: the 'disordered' region

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

Disease context

corpus callosum agenesis-abnormal genitalia syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ARX p.Met1Leu Likely pathogenic ★ same residue
ARX p.Met1Thr Likely pathogenic ★ same residue
ARX p.Arg332Gly Pathogenic/Likely pathogenic ★★ same condition
ARX p.Arg332His Pathogenic ★★ same condition
ARX p.Lys538Glu Pathogenic/Likely pathogenic ★★ same condition
ARX p.Pro353Leu Pathogenic ★★ same condition
ARX p.Ala77Thr Uncertain significance ★★ ⚠ same condition
ARX p.Leu484Phe 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/arx-p-met1arg (accessed [today's date]).

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