Is ALS2 p.Pro1016Ala (c.3046C>G) pathogenic?

ALS2 p.Pro1016Ala (c.3046C>G) is classified Conflicting classifications of pathogenicity in ALS2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.056); Rare (popmax 0.361%, afr); Associated with infantile-onset ascending hereditary spastic paralysis.

How common is ALS2 p.Pro1016Ala (c.3046C>G) in the general population?

ALS2 p.Pro1016Ala (c.3046C>G) is rare (popmax 0.361%, afr) (gnomAD).

What do computational predictors say about ALS2 p.Pro1016Ala (c.3046C>G)?

AlphaMissense predicts likely benign (score 0.056) — an in-silico prediction, not a clinical call.

ALS2 p.Pro1016Ala

Q: What condition is associated with ALS2 p.Pro1016Ala (c.3046C>G)?

ALS2 p.Pro1016Ala (c.3046C>G) is associated with infantile-onset ascending hereditary spastic paralysis, amyotrophic lateral sclerosis type 2, juvenile (ClinVar).

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.3046C>G · rs41308840 · VCV533749

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.056 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.361%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

infantile-onset ascending hereditary spastic paralysis

Computational evidence

Protein change
AlphaMissense	0.056	likely benign
REVEL	0.145	moderately benign-leaning
SaProt	LLR -5.72	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 3.4	GERP 0.094, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 56 kb · p 7.1e-07 · regional, not allelic
Overall
CADD	0.61	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 0.361% African / African-American · 271/75,016 alleles

Filtering AF 0.326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.312%

Overall 0.0315% 509/1,614,136 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.361%	277
East Asian	0.0401%	2,493
Remaining individualsnot grpmax-eligible	0.04%	2,500
Middle Eastern	0.033%	3,031
South Asian	0.0187%	5,358
Admixed American	0.0183%	5,456
European (non-Finnish)	0.0138%	7,239
Finnishnot grpmax-eligible	0.00312%	32,015

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.Pro1016Ala
Coding: c.3046C>G
MANE Select: NM_020919
dbSNP: rs41308840
Type: single nucleotide variant
Location: chr2:201726800 (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

Also linked: amyotrophic lateral sclerosis type 2, juvenile

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

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALS2 p.Pro1016Arg Uncertain significance ★★ ⚠ same residue
ALS2 p.Pro1016His Uncertain significance ★ ⚠ same residue
ALS2 p.Pro1016Thr Uncertain significance ★ ⚠ same residue
ALS2 p.Pro1016Leu 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

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-pro1016ala (accessed [today's date]).

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