Is ARX p.Pro185Leu (c.554C>T) pathogenic?

ARX p.Pro185Leu (c.554C>T) is classified Uncertain significance in ARX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-21). AlphaMissense: likely benign (0.12); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ARX p.Pro185Leu (c.554C>T)?

ARX p.Pro185Leu (c.554C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ARX p.Pro185Leu (c.554C>T) in the general population?

ARX p.Pro185Leu (c.554C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ARX p.Pro185Leu (c.554C>T)?

AlphaMissense predicts likely benign (score 0.12) — an in-silico prediction, not a clinical call.

ARX p.Pro185Leu

c.554C>T · VCV3950395

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.12 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 938,296)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.12	likely benign
REVEL	0.361	indeterminate
SaProt	LLR -6.96	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,633 bp · p 0.032 · regional, not allelic
Overall
CADD	23.1	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

No allele count reported in gnomAD v4.1 (AN 938,296). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ARX
Protein: p.Pro185Leu
Coding: c.554C>T
MANE Select: NM_139058
Type: single nucleotide variant
Location: chrX:25013441 (GRCh38)
Structure: AlphaFold pLDDT 56.51
Residue 185: 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.Pro185Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
ARX p.Pro185Ser Uncertain significance ★ ⚠ 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-pro185leu (accessed [today's date]).

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