Is ARX p.Ser31Arg (c.91A>C) pathogenic?

ARX p.Ser31Arg (c.91A>C) is classified Uncertain significance in ARX (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-03-17). AlphaMissense: likely pathogenic (0.9991); Very rare (popmax 0.000783%, nfe); Associated with Inborn genetic diseases.

How common is ARX p.Ser31Arg (c.91A>C) in the general population?

ARX p.Ser31Arg (c.91A>C) is very rare (popmax 0.000783%, nfe) (gnomAD).

What do computational predictors say about ARX p.Ser31Arg (c.91A>C)?

AlphaMissense predicts likely pathogenic (score 0.9991) — an in-silico prediction, not a clinical call.

ARX p.Ser31Arg

Q: What condition is associated with ARX p.Ser31Arg (c.91A>C)?

ARX p.Ser31Arg (c.91A>C) is associated with Inborn genetic diseases, intellectual disability, X-linked, with or without seizures, ARX-related, developmental and epileptic encephalopathy, 1 (ClinVar).

c.91A>C · rs878853107 · VCV235754

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000783%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9991	likely pathogenic · top 4% in ARX
REVEL	0.67	pathogenic-leaning
SaProt	LLR -3.86	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,633 bp · p 0.032 · regional, not allelic
Overall
CADD	26.2	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 0.000783% European (non-Finnish) · 7/894,203 alleles

Filtering AF 0.000326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000209%

Overall 0.000579% 7/1,208,250 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.Ser31Arg
Coding: c.91A>C
MANE Select: NM_139058
dbSNP: rs878853107
Type: single nucleotide variant
Location: chrX:25015647 (GRCh38)
Structure: AlphaFold pLDDT 56.51

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

Also linked: intellectual disability, X-linked, with or without seizures, ARX-related developmental and epileptic encephalopathy, 1

Similar variants

ARX p.Arg330His Likely pathogenic ★★ same condition
ARX p.Arg332Gly Pathogenic/Likely pathogenic ★★ same condition
ARX p.Arg332His Pathogenic ★★ same condition
ARX p.Arg371Gln Likely pathogenic ★★ same condition
ARX p.Arg371Ter Pathogenic ★★ same condition
ARX p.Arg384Cys Pathogenic/Likely pathogenic ★★ same condition
ARX p.Glu294Ter Pathogenic ★★ same condition
ARX p.Glu308Ter Pathogenic ★★ 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-ser31arg (accessed [today's date]).

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