Is ARSI p.Ala461= (c.1383C>T) pathogenic?

ARSI p.Ala461= (c.1383C>T) is classified Benign in ARSI (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-15). Low-frequency (popmax 3.38%, afr); Associated with Spastic paraplegia.

What condition is associated with ARSI p.Ala461= (c.1383C>T)?

ARSI p.Ala461= (c.1383C>T) is associated with Spastic paraplegia (ClinVar).

How common is ARSI p.Ala461= (c.1383C>T) in the general population?

ARSI p.Ala461= (c.1383C>T) is low-frequency (popmax 3.38%, afr) (gnomAD).

ARSI p.Ala461=

c.1383C>T · rs112583032 · VCV533758

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

low-frequency (popmax 3.38%, afr)

Conditions

Spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.7	GERP -5.1
Overall
CADD	0.239	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.38% African / African-American · 2,537/75,048 alleles

Filtering AF 3.27% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.23%

Overall 0.308% 4,974/1,613,146 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.38%	30
Middle Eastern	0.577%	173
Remaining individualsnot grpmax-eligible	0.363%	275
Admixed American	0.285%	351
European (non-Finnish)	0.168%	597
South Asian	0.0176%	5,689
Finnishnot grpmax-eligible	0.0111%	9,043
East Asian	0.00669%	14,957
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,592

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: ARSI
Protein: p.Ala461=
Coding: c.1383C>T
MANE Select: NM_001012301
dbSNP: rs112583032
Type: single nucleotide variant
Location: chr5:150297541 (GRCh38)
Gene constraint: LOEUF 1.403 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.35

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

Disease context

Spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ARSI p.Ala216Thr Uncertain significance ★★ ⚠ same condition
ARSI p.Ala259Val Uncertain significance ★★ ⚠ same condition
ARSI p.Ala264Thr Uncertain significance ★★ ⚠ same condition
ARSI p.Ala399Asp Uncertain significance ★★ ⚠ same condition
ARSI p.Ala414Ser Uncertain significance ★★ ⚠ same condition
ARSI p.Ala414Thr Uncertain significance ★★ ⚠ same condition
ARSI p.Ala78Thr Uncertain significance ★★ ⚠ same condition
ARSI p.Arg117Cys 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/arsi-p-ala461 (accessed [today's date]).

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