Is ARX p.Thr557= (c.1671G>A) pathogenic?

ARX p.Thr557= (c.1671G>A) is classified Conflicting classifications of pathogenicity in ARX (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-02-03). Rare (popmax 0.475%, nfe); Associated with intellectual disability, X-linked, with or without seizures, ARX-related.

How common is ARX p.Thr557= (c.1671G>A) in the general population?

ARX p.Thr557= (c.1671G>A) is rare (popmax 0.475%, nfe) (gnomAD).

ARX p.Thr557=

Q: What condition is associated with ARX p.Thr557= (c.1671G>A)?

ARX p.Thr557= (c.1671G>A) is associated with intellectual disability, X-linked, with or without seizures, ARX-related, developmental and epileptic encephalopathy, 1 (ClinVar).

c.1671G>A · rs190910161 · VCV96453

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

rare (popmax 0.475%, nfe)

Conditions

intellectual disability, X-linked, with or without seizures, ARX-related

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.48	GERP -0.32, phastCons 1
Overall
CADD	10.88	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.475% European (non-Finnish) · 4,147/872,386 alleles

Filtering AF 0.463% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.458%

Overall 0.406% 4,721/1,164,057 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.843%	119
European (non-Finnish)grpmax	0.475%	210
Remaining individualsnot grpmax-eligible	0.323%	310
African / African-American	0.0694%	1,440
Admixed American	0.0645%	1,551
Ashkenazi Jewishnot grpmax-eligible	0.0329%	3,037
South Asian	0.0019%	52,513

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr557=
Coding: c.1671G>A
MANE Select: NM_139058
dbSNP: rs190910161
Type: single nucleotide variant
Location: chrX:25004688 (GRCh38)
Structure: AlphaFold pLDDT 56.51

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

Disease context

intellectual disability, X-linked, with or without seizures, ARX-related — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy, 1

Similar variants

ARX p.Thr557Arg Uncertain significance ★ ⚠ same residue
ARX p.Thr557Lys Uncertain significance ★ ⚠ same residue
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

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-thr557 (accessed [today's date]).

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