Is ARSI p.Asp372His (c.1114G>C) pathogenic?

ARSI p.Asp372His (c.1114G>C) is classified Uncertain significance in ARSI (ClinVar, Single submitter, 1 submitter; last evaluated 2019-02-20). AlphaMissense: ambiguous (0.4786); Ultra-rare (popmax 0.0332%, mid); Associated with Spastic paraplegia.

What condition is associated with ARSI p.Asp372His (c.1114G>C)?

ARSI p.Asp372His (c.1114G>C) is associated with Spastic paraplegia (ClinVar).

How common is ARSI p.Asp372His (c.1114G>C) in the general population?

ARSI p.Asp372His (c.1114G>C) is ultra-rare (popmax 0.0332%, mid) (gnomAD).

What do computational predictors say about ARSI p.Asp372His (c.1114G>C)?

AlphaMissense predicts ambiguous (score 0.4786) — an in-silico prediction, not a clinical call.

ARSI p.Asp372His

c.1114G>C · rs150211860 · VCV844197

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4786 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0332%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.4786	ambiguous
REVEL	0.732	pathogenic-leaning
SaProt	LLR -12.25	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense 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	21.2	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 0.0332% Middle Eastern · 2/6,032 alleles

Filtering AF 0.00584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00243%

Overall 0.000138% 2/1,454,060 alleles · ultra-rare

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.Asp372His
Coding: c.1114G>C
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

Similar variants

ARSI p.Asp372Asn 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-asp372his (accessed [today's date]).

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