Is ARSI p.Arg314Cys (c.940C>T) pathogenic?

ARSI p.Arg314Cys (c.940C>T) is classified Uncertain significance in ARSI (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-08). AlphaMissense: ambiguous (0.4595); Ultra-rare (popmax 0.01%, amr); Associated with Spastic paraplegia.

What condition is associated with ARSI p.Arg314Cys (c.940C>T)?

ARSI p.Arg314Cys (c.940C>T) is associated with Spastic paraplegia (ClinVar).

How common is ARSI p.Arg314Cys (c.940C>T) in the general population?

ARSI p.Arg314Cys (c.940C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about ARSI p.Arg314Cys (c.940C>T)?

AlphaMissense predicts ambiguous (score 0.4595) — an in-silico prediction, not a clinical call.

ARSI p.Arg314Cys

c.940C>T · rs776520005 · VCV1464949

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4595 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.4595	ambiguous
REVEL	0.719	pathogenic-leaning
SaProt	LLR -8.18	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP -0.78, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 5,156 bp · p 0.021 · regional, not allelic
Overall
CADD	24.7	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 0.01% Admixed American · 6/59,956 alleles

Filtering AF 0.00429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00161% 26/1,612,548 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,993
African / African-American	0.00668%	14,981
South Asian	0.00329%	30,351
Finnishnot grpmax-eligible	0.00159%	62,862
European (non-Finnish)	0.000932%	107,261

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.Arg314Cys
Coding: c.940C>T
MANE Select: NM_001012301
dbSNP: rs776520005
Type: single nucleotide variant
Location: chr5:150297984 (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

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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-arg314cys (accessed [today's date]).

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