Is ARSI p.Leu126= (c.378G>A) pathogenic?

ARSI p.Leu126= (c.378G>A) is classified Benign in ARSI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-28). Rare (popmax 0.312%, afr); Associated with Spastic paraplegia.

What condition is associated with ARSI p.Leu126= (c.378G>A)?

ARSI p.Leu126= (c.378G>A) is associated with Spastic paraplegia (ClinVar).

How common is ARSI p.Leu126= (c.378G>A) in the general population?

ARSI p.Leu126= (c.378G>A) is rare (popmax 0.312%, afr) (gnomAD).

ARSI p.Leu126=

c.378G>A · rs113307962 · VCV705995

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.312%, 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 2.3	GERP 1.6, phastCons 1
Overall
CADD	12.35	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.312% African / African-American · 234/75,052 alleles

Filtering AF 0.279% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.266%

Overall 0.018% 290/1,614,038 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.312%	321
Remaining individualsnot grpmax-eligible	0.0336%	2,976
Admixed American	0.0317%	3,159
Middle Eastern	0.0165%	6,046
European (non-Finnish)	0.00127%	78,662

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.Leu126=
Coding: c.378G>A
MANE Select: NM_001012301
dbSNP: rs113307962
Type: single nucleotide variant
Location: chr5:150298546 (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-leu126 (accessed [today's date]).

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