Is ARSI p.Pro375= (c.1125G>A) pathogenic?

ARSI p.Pro375= (c.1125G>A) is classified Likely benign in ARSI (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-12). Very rare (popmax 0.00504%, amr); Associated with Spastic paraplegia.

What condition is associated with ARSI p.Pro375= (c.1125G>A)?

ARSI p.Pro375= (c.1125G>A) is associated with Spastic paraplegia (ClinVar).

How common is ARSI p.Pro375= (c.1125G>A) in the general population?

ARSI p.Pro375= (c.1125G>A) is very rare (popmax 0.00504%, amr) (gnomAD).

ARSI p.Pro375=

c.1125G>A · VCV3702785

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00504%, amr)

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 -9.7	GERP -5.1
Overall
CADD	0.25	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00504% Admixed American · 3/59,502 alleles

Filtering AF 0.00134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000671%

Overall 0.00106% 17/1,604,526 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00504%	19,834
African / African-American	0.00401%	24,915
South Asian	0.00222%	44,999
European (non-Finnish)	0.000766%	130,522

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.Pro375=
Coding: c.1125G>A
MANE Select: NM_001012301
Type: single nucleotide variant
Location: chr5:150297799 (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-pro375 (accessed [today's date]).

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