Is ALS2 p.Arg1302His (c.3905G>A) pathogenic?

ALS2 p.Arg1302His (c.3905G>A) is classified Likely benign in ALS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-01). AlphaMissense: likely benign (0.0524); Rare (popmax 0.364%, afr); Associated with amyotrophic lateral sclerosis type 2, juvenile.

What condition is associated with ALS2 p.Arg1302His (c.3905G>A)?

ALS2 p.Arg1302His (c.3905G>A) is associated with amyotrophic lateral sclerosis type 2, juvenile, infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 p.Arg1302His (c.3905G>A) in the general population?

ALS2 p.Arg1302His (c.3905G>A) is rare (popmax 0.364%, afr) (gnomAD).

How is Juvenile amyotrophic lateral sclerosis inherited?

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

What do computational predictors say about ALS2 p.Arg1302His (c.3905G>A)?

AlphaMissense predicts likely benign (score 0.0524) — an in-silico prediction, not a clinical call.

ALS2 p.Arg1302His

c.3905G>A · rs199577696 · VCV696111

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0524 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.364%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis type 2, juvenile

Computational evidence

Protein change
AlphaMissense	0.0524	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	LLR -7.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.2	GERP -3.4
Regional constraint	o/e 0.87	unconstrained · MANE · 56 kb · p 7.1e-07 · regional, not allelic
Overall
CADD	11.44	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 0.364% African / African-American · 273/75,048 alleles

Filtering AF 0.328% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.314%

Overall 0.0195% 315/1,614,188 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.364%	275
Remaining individualsnot grpmax-eligible	0.032%	3,125
Admixed American	0.0183%	5,457
East Asian	0.00446%	22,438
South Asian	0.0022%	45,538
European (non-Finnish)	0.000593%	168,577

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.Arg1302His
Coding: c.3905G>A
MANE Select: NM_020919
dbSNP: rs199577696
Type: single nucleotide variant
Location: chr2:201715771 (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

amyotrophic lateral sclerosis type 2, juvenile — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: infantile-onset ascending hereditary spastic paralysis

For Juvenile amyotrophic lateral sclerosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

ALS2 p.Arg1302Cys 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 c.4626+1G>A 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-arg1302his (accessed [today's date]).

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