Is ARX p.Arg204Ser (c.610C>A) pathogenic?

ARX p.Arg204Ser (c.610C>A) is classified Uncertain significance in ARX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-14). AlphaMissense: likely benign (0.1664); Very rare (popmax 0.00213%, sas); Associated with developmental and epileptic encephalopathy, 1.

What condition is associated with ARX p.Arg204Ser (c.610C>A)?

ARX p.Arg204Ser (c.610C>A) is associated with developmental and epileptic encephalopathy, 1, intellectual disability, X-linked, with or without seizures, ARX-related (ClinVar).

How common is ARX p.Arg204Ser (c.610C>A) in the general population?

ARX p.Arg204Ser (c.610C>A) is very rare (popmax 0.00213%, sas) (gnomAD).

How is Infantile epileptic spasms syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ARX p.Arg204Ser (c.610C>A)?

AlphaMissense predicts likely benign (score 0.1664) — an in-silico prediction, not a clinical call.

ARX p.Arg204Ser

c.610C>A · rs777162737 · VCV1513783

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1664 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00213%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 1

Computational evidence

Protein change
AlphaMissense	0.1664	likely benign
REVEL	0.2	benign-leaning
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 0.56, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,633 bp · p 0.032 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00213% South Asian · 1/47,050 alleles

Filtering AF 0.000109% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.4e-05%

Overall 0.000537% 6/1,118,294 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00227%	44,085
South Asiangrpmax	0.00213%	47,050
European (non-Finnish)	0.000467%	214,259

Remaining individuals 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.Arg204Ser
Coding: c.610C>A
MANE Select: NM_139058
dbSNP: rs777162737
Type: single nucleotide variant
Location: chrX:25013385 (GRCh38)
Structure: AlphaFold pLDDT 56.51
Residue 204: the 'disordered' region

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

Disease context

developmental and epileptic encephalopathy, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Infantile epileptic spasms syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked dominant

Similar variants

ARX p.Arg204Pro Uncertain significance ★★ ⚠ same residue
ARX p.Arg204His Conflicting classifications of pathogenicity ★ ⚠ same residue
ARX p.Arg204Leu Uncertain significance ★ ⚠ same residue
ARX p.Arg204Cys 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

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-arg204ser (accessed [today's date]).

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