Is ARX p.Pro291Ser (c.871C>T) pathogenic?

ARX p.Pro291Ser (c.871C>T) is classified Uncertain significance in ARX (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-05). AlphaMissense: ambiguous (0.4442); Very rare (popmax 0.000336%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ARX p.Pro291Ser (c.871C>T)?

ARX p.Pro291Ser (c.871C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ARX p.Pro291Ser (c.871C>T) in the general population?

ARX p.Pro291Ser (c.871C>T) is very rare (popmax 0.000336%, nfe) (gnomAD).

What do computational predictors say about ARX p.Pro291Ser (c.871C>T)?

AlphaMissense predicts ambiguous (score 0.4442) — an in-silico prediction, not a clinical call.

ARX p.Pro291Ser

c.871C>T · rs1215880809 · VCV2609796

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4442 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000336%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4442	ambiguous
REVEL	0.313	indeterminate
SaProt	LLR -6.58	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,633 bp · p 0.032 · regional, not allelic
Overall
CADD	23.7	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 0.000336% European (non-Finnish) · 3/891,585 alleles

Filtering AF 9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000276% 3/1,088,820 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.Pro291Ser
Coding: c.871C>T
MANE Select: NM_139058
dbSNP: rs1215880809
Type: single nucleotide variant
Location: chrX:25013124 (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

Similar variants

ARX p.Pro291= 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
ARX p.Pro135Leu 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-pro291ser (accessed [today's date]).

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