Is ARSI p.Glu379Lys (c.1135G>A) pathogenic?

ARSI p.Glu379Lys (c.1135G>A) is classified Conflicting classifications of pathogenicity in ARSI (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.1404); Ultra-rare (popmax 0.0522%, sas); Associated with Spastic paraplegia.

What condition is associated with ARSI p.Glu379Lys (c.1135G>A)?

ARSI p.Glu379Lys (c.1135G>A) is associated with Spastic paraplegia (ClinVar).

How common is ARSI p.Glu379Lys (c.1135G>A) in the general population?

ARSI p.Glu379Lys (c.1135G>A) is ultra-rare (popmax 0.0522%, sas) (gnomAD).

What do computational predictors say about ARSI p.Glu379Lys (c.1135G>A)?

AlphaMissense predicts likely benign (score 0.1404) — an in-silico prediction, not a clinical call.

ARSI p.Glu379Lys

c.1135G>A · rs200384227 · VCV644364

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1404 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0522%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.1404	likely benign
REVEL	0.723	pathogenic-leaning
SaProt	LLR -9.38	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 5,156 bp · p 0.021 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0522% South Asian · 47/90,024 alleles

Filtering AF 0.0412% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.04%

Overall 0.0384% 616/1,604,602 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0522%	1,915
European (non-Finnish)	0.0444%	2,255
Finnishnot grpmax-eligible	0.0414%	2,416
Remaining individualsnot grpmax-eligible	0.0145%	6,897
African / African-American	0.00935%	10,698
Admixed American	0.00672%	14,877
Ashkenazi Jewishnot grpmax-eligible	0.00345%	29,022
East Asian	0.00224%	44,732

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.Glu379Lys
Coding: c.1135G>A
MANE Select: NM_001012301
dbSNP: rs200384227
Type: single nucleotide variant
Location: chr5:150297789 (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-glu379lys (accessed [today's date]).

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