Is ARSA p.Val93Ile (c.277G>A) pathogenic?

ARSA p.Val93Ile (c.277G>A) is classified Uncertain significance in ARSA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-16). Very rare (popmax 0.00128%, nfe).

How common is ARSA p.Val93Ile (c.277G>A) in the general population?

ARSA p.Val93Ile (c.277G>A) is very rare (popmax 0.00128%, nfe) (gnomAD).

ARSA p.Val93Ile

c.277G>A · VCV4948513

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00128%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.688	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,631 bp · p 0.96 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00128% European (non-Finnish) · 15/1,174,774 alleles

Filtering AF 0.000767% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000608%

Overall 0.00113% 18/1,599,462 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00323%	30,964
European (non-Finnish)grpmax	0.00128%	78,318
South Asian	0.00112%	89,388

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: ARSA
Protein: p.Val93Ile
Coding: c.277G>A
MANE Select: NM_000487
Type: single nucleotide variant
Location: chr22:50627354 (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

Similar variants

ARSA p.Val93= Conflicting classifications of pathogenicity ★ same residue
ARSA p.Val93Gly Uncertain significance ★ same residue
ARSA c.1107+1G>A Pathogenic/Likely pathogenic ★★ same type
ARSA c.1107+1G>T Pathogenic ★★ same type
ARSA c.1108-2A>G Pathogenic ★★ same type
ARSA c.1108-3C>G Pathogenic/Likely pathogenic ★★ same type
ARSA c.1210+1G>A Pathogenic ★★ same type
ARSA c.224+1G>A Likely pathogenic ★★ 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/arsa-p-val93ile (accessed [today's date]).

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