Is ARX p.Ser72Arg (c.216C>A) pathogenic?

ARX p.Ser72Arg (c.216C>A) is classified Conflicting classifications of pathogenicity in ARX (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2021-08-04). AlphaMissense: likely pathogenic (0.5803); Very rare (popmax 0.000133%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ARX p.Ser72Arg (c.216C>A)?

ARX p.Ser72Arg (c.216C>A) is associated with Inborn genetic diseases (ClinVar).

How common is ARX p.Ser72Arg (c.216C>A) in the general population?

ARX p.Ser72Arg (c.216C>A) is very rare (popmax 0.000133%, nfe) (gnomAD).

What do computational predictors say about ARX p.Ser72Arg (c.216C>A)?

AlphaMissense predicts likely pathogenic (score 0.5803) — an in-silico prediction, not a clinical call.

ARX p.Ser72Arg

c.216C>A · rs587783195 · VCV157752

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5803 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000133%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5803	likely pathogenic
REVEL	0.143	moderately benign-leaning
SaProt	LLR -6.78	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP -1.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,633 bp · p 0.032 · regional, not allelic
Overall
CADD	14.33	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 0.000133% European (non-Finnish) · 1/750,072 alleles

Overall 0.000123% 1/815,740 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.Ser72Arg
Coding: c.216C>A
MANE Select: NM_139058
dbSNP: rs587783195
Type: single nucleotide variant
Location: chrX:25013779 (GRCh38)
Structure: AlphaFold pLDDT 56.51
Residue 72: the 'disordered' region

Full ARX 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

ARX p.Ser72Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
ARX p.Ser72= Likely benign ★ same residue
ARX p.Glu308Ter Pathogenic ★★ same condition
ARX c.196+6G>A Uncertain significance ★★ same condition
ARX p.Ala149Val Uncertain significance ★★ ⚠ same condition
ARX p.Arg204Cys Uncertain significance ★★ ⚠ same condition
ARX p.Gly34Ala Uncertain significance ★★ ⚠ same condition
ARX p.Leu159Phe 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-ser72arg (accessed [today's date]).

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