Is ARSI p.Asp372Asn (c.1114G>A) pathogenic?

ARSI p.Asp372Asn (c.1114G>A) is classified Uncertain significance in ARSI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-07). AlphaMissense: likely benign (0.0793); Rare (popmax 0.145%, nfe); Associated with Spastic paraplegia.

What condition is associated with ARSI p.Asp372Asn (c.1114G>A)?

ARSI p.Asp372Asn (c.1114G>A) is associated with Spastic paraplegia, hereditary spastic paraplegia (ClinVar).

How common is ARSI p.Asp372Asn (c.1114G>A) in the general population?

ARSI p.Asp372Asn (c.1114G>A) is rare (popmax 0.145%, nfe) (gnomAD).

What do computational predictors say about ARSI p.Asp372Asn (c.1114G>A)?

AlphaMissense predicts likely benign (score 0.0793) — an in-silico prediction, not a clinical call.

ARSI p.Asp372Asn

c.1114G>A · rs150211860 · VCV424672

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0793 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.145%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.0793	likely benign
REVEL	0.33	indeterminate
SaProt	LLR -6.86	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 2.2	GERP 1.5, phastCons 0.98
Regional constraint	o/e 0.92	unconstrained · MANE · 5,156 bp · p 0.021 · regional, not allelic
Overall
CADD	15.46	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 0.145% European (non-Finnish) · 1,711/1,176,004 alleles

Filtering AF 0.14% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.137%

Overall 0.115% 1,844/1,606,244 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.145%	687
Remaining individualsnot grpmax-eligible	0.0692%	1,445
South Asian	0.0511%	1,957
Admixed American	0.0218%	4,586
African / African-American	0.0214%	4,676
Finnishnot grpmax-eligible	0.0207%	4,832
East Asian	0.00447%	22,396

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.Asp372Asn
Coding: c.1114G>A
MANE Select: NM_001012301
dbSNP: rs150211860
Type: single nucleotide variant
Location: chr5:150297810 (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

Also linked: hereditary spastic paraplegia

Similar variants

ARSI p.Asp372His Uncertain significance ★ ⚠ same residue
ARSI p.Asp372= Likely benign ★ 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-asp372asn (accessed [today's date]).

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