Is ARSL p.Arg111His (c.332G>A) pathogenic?

ARSL p.Arg111His (c.332G>A) is classified Likely pathogenic in ARSL (ClinVar, Single submitter, 1 submitter; last evaluated 2016-08-19). AlphaMissense: likely benign (0.2936); Very rare (popmax 0.000112%, nfe).

How common is ARSL p.Arg111His (c.332G>A) in the general population?

ARSL p.Arg111His (c.332G>A) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about ARSL p.Arg111His (c.332G>A)?

AlphaMissense predicts likely benign (score 0.2936) — an in-silico prediction, not a clinical call.

ARSL p.Arg111His

c.332G>A · rs122460153 · VCV372304

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2936 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2936	likely benign ⚠ discordant with ClinVar
REVEL	0.677	pathogenic-leaning
SaProt	LLR -5.89	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 1.1, phastCons 0.99
Regional constraint	o/e 0.63	unconstrained · MANE · 26 kb · p 8.2e-17 · regional, not allelic
Overall
CADD	20.5	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 0.000112% European (non-Finnish) · 1/893,832 alleles

Overall 0.00089% 1/112,326 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: ARSL
Protein: p.Arg111His
Coding: c.332G>A
MANE Select: NM_000047
dbSNP: rs122460153
Type: single nucleotide variant
Location: chrX:2953241 (GRCh38)
Structure: AlphaFold pLDDT 92.57
Residue 111: a UniProt-annotated variant site (in cdpx1; significant loss of arylsulfatase activity; no effect on protein stability and localization to the golgi apparatus)

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

Similar variants

ARSL p.Arg111Cys Likely pathogenic ★★ same residue
ARSL p.Arg111Pro Pathogenic ⚠ same residue
ARSL c.1289+1G>A Pathogenic/Likely pathogenic ★★ same type
ARSL c.24-2A>G Likely pathogenic ★★ same type
ARSL p.Gly117Arg Pathogenic/Likely pathogenic ★★ same type
ARSL p.Gly73Ser Likely pathogenic ★★ ⚠ same type
ARSL p.Ala182Thr Uncertain significance ★★ ⚠ same type
ARSL p.Ala251Val Uncertain significance ★★ ⚠ same type

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/arsl-p-arg111his (accessed [today's date]).

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