Is ARSI p.Arg283His (c.848G>A) pathogenic?

ARSI p.Arg283His (c.848G>A) is classified Uncertain significance in ARSI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-22). AlphaMissense: likely benign (0.0908); Ultra-rare (popmax 0.08%, afr); Associated with Spastic paraplegia.

What condition is associated with ARSI p.Arg283His (c.848G>A)?

ARSI p.Arg283His (c.848G>A) is associated with Spastic paraplegia (ClinVar).

How common is ARSI p.Arg283His (c.848G>A) in the general population?

ARSI p.Arg283His (c.848G>A) is ultra-rare (popmax 0.08%, afr) (gnomAD).

What do computational predictors say about ARSI p.Arg283His (c.848G>A)?

AlphaMissense predicts likely benign (score 0.0908) — an in-silico prediction, not a clinical call.

ARSI p.Arg283His

c.848G>A · rs149948064 · VCV959793

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0908 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.08%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.0908	likely benign
REVEL	0.438	indeterminate
SaProt	LLR -7.03	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -0.71, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 5,156 bp · p 0.021 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.08% African / African-American · 60/74,976 alleles

Filtering AF 0.0638% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0579%

Overall 0.00738% 119/1,613,182 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.08%	1,250
Middle Eastern	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.0048%	20,833
European (non-Finnish)	0.00415%	24,082
Admixed American	0.00333%	30,004
South Asian	0.00329%	30,354
East Asian	0.00223%	44,866

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.Arg283His
Coding: c.848G>A
MANE Select: NM_001012301
dbSNP: rs149948064
Type: single nucleotide variant
Location: chr5:150298076 (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.Arg283Cys Uncertain significance ★★ ⚠ same residue
ARSI p.Arg283Leu 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

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-arg283his (accessed [today's date]).

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