Is ARSI p.Arg339Trp (c.1015C>T) pathogenic?

ARSI p.Arg339Trp (c.1015C>T) is classified Uncertain significance in ARSI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-03). AlphaMissense: likely benign (0.1603); Ultra-rare (popmax 0.056%, afr); Associated with Spastic paraplegia.

What condition is associated with ARSI p.Arg339Trp (c.1015C>T)?

ARSI p.Arg339Trp (c.1015C>T) is associated with Spastic paraplegia (ClinVar).

How common is ARSI p.Arg339Trp (c.1015C>T) in the general population?

ARSI p.Arg339Trp (c.1015C>T) is ultra-rare (popmax 0.056%, afr) (gnomAD).

What do computational predictors say about ARSI p.Arg339Trp (c.1015C>T)?

AlphaMissense predicts likely benign (score 0.1603) — an in-silico prediction, not a clinical call.

ARSI p.Arg339Trp

c.1015C>T · rs149628658 · VCV1988402

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1603 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.056%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.1603	likely benign
REVEL	0.658	pathogenic-leaning
SaProt	LLR -7.87	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 2.2	GERP -4.7, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 5,156 bp · p 0.021 · regional, not allelic
Overall
CADD	22.6	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 0.056% African / African-American · 42/75,016 alleles

Filtering AF 0.0425% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0378%

Overall 0.0284% 457/1,611,856 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.056%	1,786
Middle Eastern	0.033%	3,026
European (non-Finnish)	0.0312%	3,204
East Asian	0.0267%	3,739
Remaining individualsnot grpmax-eligible	0.0208%	4,803
South Asian	0.0132%	7,578
Finnishnot grpmax-eligible	0.00635%	15,758
Admixed American	0.005%	19,984
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,480

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.Arg339Trp
Coding: c.1015C>T
MANE Select: NM_001012301
dbSNP: rs149628658
Type: single nucleotide variant
Location: chr5:150297909 (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-arg339trp (accessed [today's date]).

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