Is ARSI p.Arg161His (c.482G>A) pathogenic?

ARSI p.Arg161His (c.482G>A) is classified Uncertain significance in ARSI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: likely benign (0.099); Very rare (popmax 0.00667%, afr); Associated with Spastic paraplegia.

What condition is associated with ARSI p.Arg161His (c.482G>A)?

ARSI p.Arg161His (c.482G>A) is associated with Spastic paraplegia (ClinVar).

How common is ARSI p.Arg161His (c.482G>A) in the general population?

ARSI p.Arg161His (c.482G>A) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about ARSI p.Arg161His (c.482G>A)?

AlphaMissense predicts likely benign (score 0.099) — an in-silico prediction, not a clinical call.

ARSI p.Arg161His

c.482G>A · rs142729073 · VCV1026125

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.099 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.099	likely benign
REVEL	0.764	pathogenic-leaning
SaProt	LLR -5.87	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 4.9	GERP -1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 5,156 bp · p 0.021 · regional, not allelic
Overall
CADD	24.2	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 0.00667% African / African-American · 5/74,924 alleles

Filtering AF 0.00443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00403%

Overall 0.00471% 76/1,614,090 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,985
European (non-Finnish)	0.00551%	18,155
East Asian	0.00445%	22,449
Admixed American	0.00333%	30,007
Remaining individualsnot grpmax-eligible	0.0032%	31,243

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.Arg161His
Coding: c.482G>A
MANE Select: NM_001012301
dbSNP: rs142729073
Type: single nucleotide variant
Location: chr5:150298442 (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

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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-arg161his (accessed [today's date]).

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