Is ALS2 p.Ile94Val (c.280A>G) pathogenic?

ALS2 p.Ile94Val (c.280A>G) is classified Benign in ALS2 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0548); Common (popmax 5.09%, afr) — too common for a highly-penetrant pathogenic allele; Associated with infantile-onset ascending hereditary spastic paralysis.

What condition is associated with ALS2 p.Ile94Val (c.280A>G)?

ALS2 p.Ile94Val (c.280A>G) is associated with infantile-onset ascending hereditary spastic paralysis, amyotrophic lateral sclerosis type 2, juvenile, hereditary spastic paraplegia (ClinVar).

What do computational predictors say about ALS2 p.Ile94Val (c.280A>G)?

AlphaMissense predicts likely benign (score 0.0548) — an in-silico prediction, not a clinical call.

ALS2 p.Ile94Val

Q: How common is ALS2 p.Ile94Val (c.280A>G) in the general population?

ALS2 p.Ile94Val (c.280A>G) is common (popmax 5.09%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.280A>G · rs3219154 · VCV261370

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0548 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.09%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

infantile-onset ascending hereditary spastic paralysis

Computational evidence

Protein change
AlphaMissense	0.0548	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -3.86	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 1.8	GERP 0.02, phastCons 0.93
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0064 · regional, not allelic
Overall
CADD	12.25	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 5.09% African / African-American · 3,815/74,962 alleles

Filtering AF 4.95% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.9%

Overall 2.89% 46,579/1,613,992 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.09%	20
Ashkenazi Jewishnot grpmax-eligible	4.88%	20
European (non-Finnish)	2.93%	34
Remaining individualsnot grpmax-eligible	2.8%	36
South Asian	2.56%	39
Finnishnot grpmax-eligible	2.27%	44
Amishnot grpmax-eligible	1.86%	54
Middle Eastern	1.77%	57
Admixed American	1.72%	58
East Asian	0.0513%	1,951

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.Ile94Val
Coding: c.280A>G
MANE Select: NM_020919
dbSNP: rs3219154
Type: single nucleotide variant
Location: chr2:201761714 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.69
Residue 94: a UniProt-annotated variant site (in)

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

Also linked: amyotrophic lateral sclerosis type 2, juvenile hereditary spastic paraplegia

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

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALS2 p.Ile94Ser 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-ile94val (accessed [today's date]).

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