Is ARSA p.His140fs (c.418dup) pathogenic?

ARSA p.His140fs (c.418dup) is classified Pathogenic in ARSA (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-09-17). Ultra-rare (popmax 0.0334%, afr); Associated with Inborn genetic diseases.

What condition is associated with ARSA p.His140fs (c.418dup)?

ARSA p.His140fs (c.418dup) is associated with Inborn genetic diseases, metachromatic leukodystrophy (ClinVar).

How common is ARSA p.His140fs (c.418dup) in the general population?

ARSA p.His140fs (c.418dup) is ultra-rare (popmax 0.0334%, afr) (gnomAD).

ARSA p.His140fs

c.418dup · rs745884435 · VCV370305

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.3	GERP 2, phastCons 1
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0334% African / African-American · 25/74,842 alleles

Filtering AF 0.0232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0198%

Overall 0.00496% 80/1,612,020 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0334%	2,994
Finnishnot grpmax-eligible	0.0222%	4,511
Remaining individualsnot grpmax-eligible	0.00641%	15,602
Admixed American	0.00334%	29,936
South Asian	0.0033%	30,329
European (non-Finnish)	0.00271%	36,856

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: ARSA
Protein: p.His140fs
Coding: c.418dup
MANE Select: NM_000487
dbSNP: rs745884435
Type: Duplication
Location: chr22:50627212 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB

Full ARSA 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

Also linked: metachromatic leukodystrophy

Similar variants

ARSA p.His140Asp Pathogenic/Likely pathogenic ★★ same residue
ARSA p.His140Leu Uncertain significance ★★ same residue
ARSA p.His140Tyr Uncertain significance ★ same residue
ARSA p.Arg498fs Pathogenic/Likely pathogenic ★★ same condition
ARSA p.Arg99fs Pathogenic ★★ same condition
ARSA p.Gly449fs Pathogenic ★★ same condition
ARSA p.Gly81fs Pathogenic/Likely pathogenic ★★ same condition
ARSA p.Leu183fs 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/arsa-p-his140fs (accessed [today's date]).

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