Is ARSI p.Arg474Pro (c.1421G>C) pathogenic?

ARSI p.Arg474Pro (c.1421G>C) is classified Uncertain significance in ARSI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-13). AlphaMissense: likely pathogenic (0.9794); Ultra-rare (popmax 0.0893%, afr); Associated with Spastic paraplegia.

What condition is associated with ARSI p.Arg474Pro (c.1421G>C)?

ARSI p.Arg474Pro (c.1421G>C) is associated with Spastic paraplegia (ClinVar).

How common is ARSI p.Arg474Pro (c.1421G>C) in the general population?

ARSI p.Arg474Pro (c.1421G>C) is ultra-rare (popmax 0.0893%, afr) (gnomAD).

What do computational predictors say about ARSI p.Arg474Pro (c.1421G>C)?

AlphaMissense predicts likely pathogenic (score 0.9794) — an in-silico prediction, not a clinical call.

ARSI p.Arg474Pro

c.1421G>C · rs149473787 · VCV1021329

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9794 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0893%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.9794	likely pathogenic · top 9% in ARSI
REVEL	0.865	moderately pathogenic-leaning
SaProt	LLR -12.55	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 5,156 bp · p 0.021 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0893% African / African-American · 67/75,048 alleles

Filtering AF 0.0721% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0658%

Overall 0.00496% 80/1,613,824 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0893%	1,120
Admixed American	0.0133%	7,500
Remaining individualsnot grpmax-eligible	0.008%	12,499

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.Arg474Pro
Coding: c.1421G>C
MANE Select: NM_001012301
dbSNP: rs149473787
Type: single nucleotide variant
Location: chr5:150297503 (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.Arg474Gln Uncertain significance ★★ ⚠ same residue
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

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-arg474pro (accessed [today's date]).

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