Is ARSA p.His208= (c.624T>C) pathogenic?

ARSA p.His208= (c.624T>C) is classified Benign/Likely benign in ARSA (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-06-01). Low-frequency (popmax 1.01%, nfe); Associated with metachromatic leukodystrophy.

What condition is associated with ARSA p.His208= (c.624T>C)?

ARSA p.His208= (c.624T>C) is associated with metachromatic leukodystrophy (ClinVar).

How common is ARSA p.His208= (c.624T>C) in the general population?

ARSA p.His208= (c.624T>C) is low-frequency (popmax 1.01%, nfe) (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

ARSA p.His208=

c.624T>C · rs113990230 · VCV256246

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.01%, nfe)

Conditions

metachromatic leukodystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP -5	GERP -4.3
Overall
CADD	0.135	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.01% European (non-Finnish) · 11,872/1,179,948 alleles

Filtering AF 0.991% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.985%

Overall 0.907% 14,633/1,613,476 alleles · low-frequency

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	2.88%	35
European (non-Finnish)grpmax	1.01%	99
Ashkenazi Jewishnot grpmax-eligible	0.794%	126
Remaining individualsnot grpmax-eligible	0.72%	139
Admixed American	0.283%	353
African / African-American	0.096%	1,042
Middle Eastern	0.0165%	6,062
South Asian	0.00439%	22,769

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: ARSA
Protein: p.His208=
Coding: c.624T>C
MANE Select: NM_000487
dbSNP: rs113990230
Type: single nucleotide variant
Location: chr22:50626894 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB
Residue 208: an α-helix

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

Disease context

metachromatic leukodystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Metachromatic leukodystrophy (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

ARSA p.His208fs Pathogenic ★★ same residue
ARSA c.1107+1G>A Pathogenic/Likely pathogenic ★★ same condition
ARSA c.1107+1G>T Pathogenic ★★ same condition
ARSA c.1108-2A>G Pathogenic ★★ same condition
ARSA c.1108-3C>G Pathogenic/Likely pathogenic ★★ same condition
ARSA c.1210+1G>A Pathogenic ★★ same condition
ARSA c.224+1G>A Likely pathogenic ★★ same condition
ARSA c.225-1G>C 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/arsa-p-his208 (accessed [today's date]).

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