Is ALS2 p.Arg1132His (c.3395G>A) pathogenic?

ALS2 p.Arg1132His (c.3395G>A) is classified Uncertain significance in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-27). AlphaMissense: likely pathogenic (0.7781); Very rare (popmax 0.00666%, amr); Associated with infantile-onset ascending hereditary spastic paralysis.

What condition is associated with ALS2 p.Arg1132His (c.3395G>A)?

ALS2 p.Arg1132His (c.3395G>A) is associated with infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 p.Arg1132His (c.3395G>A) in the general population?

ALS2 p.Arg1132His (c.3395G>A) is very rare (popmax 0.00666%, amr) (gnomAD).

What do computational predictors say about ALS2 p.Arg1132His (c.3395G>A)?

AlphaMissense predicts likely pathogenic (score 0.7781) — an in-silico prediction, not a clinical call.

ALS2 p.Arg1132His

Q: How is Infantile-onset ascending hereditary spastic paralysis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.3395G>A · rs753713733 · VCV1398138

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7781 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

infantile-onset ascending hereditary spastic paralysis

Computational evidence

Protein change
AlphaMissense	0.7781	likely pathogenic
REVEL	0.446	indeterminate
SaProt	LLR -10.55	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 56 kb · p 7.1e-07 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00666% Admixed American · 4/60,024 alleles

Filtering AF 0.00225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000958% 14/1,461,708 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00666%	15,006
South Asian	0.0011%	91,070
European (non-Finnish)	0.000763%	131,099

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: ALS2
Protein: p.Arg1132His
Coding: c.3395G>A
MANE Select: NM_020919
dbSNP: rs753713733
Type: single nucleotide variant
Location: chr2:201724412 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.69

Full ALS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

infantile-onset ascending hereditary spastic paralysis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Infantile-onset ascending hereditary spastic paralysis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALS2 p.Arg1132Cys Uncertain significance ★★ ⚠ same residue
ALS2 p.Arg1132Ser Uncertain significance ★ ⚠ same residue
ALS2 c.1640+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALS2 c.2580+2T>C Pathogenic ★★ same condition
ALS2 c.3703-2A>G Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Ala573Glu Likely pathogenic ★★ same condition
ALS2 p.Arg1139Ter Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Arg1421Ter Pathogenic/Likely pathogenic ★★ 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/als2-p-arg1132his (accessed [today's date]).

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