Is ALS2 p.Pro550= (c.1650G>A) pathogenic?

ALS2 p.Pro550= (c.1650G>A) is classified Likely benign in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-16). Ultra-rare (popmax 0.0164%, mid); Associated with infantile-onset ascending hereditary spastic paralysis.

What condition is associated with ALS2 p.Pro550= (c.1650G>A)?

ALS2 p.Pro550= (c.1650G>A) is associated with infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 p.Pro550= (c.1650G>A) in the general population?

ALS2 p.Pro550= (c.1650G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

ALS2 p.Pro550=

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.1650G>A · rs749442386 · VCV1576100

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

infantile-onset ascending hereditary spastic paralysis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.3	GERP -3.5
Overall
CADD	10.72	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.00341% 55/1,613,628 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.00439%	22,769
European (non-Finnish)	0.00398%	25,100
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
Finnishnot grpmax-eligible	0.00156%	64,002
African / African-American	0.00133%	74,914

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.Pro550=
Coding: c.1650G>A
MANE Select: NM_020919
dbSNP: rs749442386
Type: single nucleotide variant
Location: chr2:201753233 (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.Pro550Leu Likely pathogenic ★★ 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
ALS2 p.Arg1461Ter 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-pro550 (accessed [today's date]).

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