Is ALS2 p.Pro192Leu (c.575C>T) pathogenic?

ALS2 p.Pro192Leu (c.575C>T) is classified Conflicting classifications of pathogenicity in ALS2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-27). AlphaMissense: likely pathogenic (0.9016); Very rare (popmax 0.00669%, amr); Associated with infantile-onset ascending hereditary spastic paralysis.

What condition is associated with ALS2 p.Pro192Leu (c.575C>T)?

ALS2 p.Pro192Leu (c.575C>T) is associated with infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 p.Pro192Leu (c.575C>T) in the general population?

ALS2 p.Pro192Leu (c.575C>T) is very rare (popmax 0.00669%, amr) (gnomAD).

What do computational predictors say about ALS2 p.Pro192Leu (c.575C>T)?

AlphaMissense predicts likely pathogenic (score 0.9016) — an in-silico prediction, not a clinical call.

ALS2 p.Pro192Leu

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.575C>T · rs778003334 · VCV988998

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9016 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

infantile-onset ascending hereditary spastic paralysis

Computational evidence

Protein change
AlphaMissense	0.9016	likely pathogenic
REVEL	0.946	strongly pathogenic-leaning
SaProt	LLR -10.82	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0064 · regional, not allelic
Overall
CADD	33.0	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 0.00669% Admixed American · 4/59,832 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000684% 11/1,607,624 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00669%	14,958
Remaining individualsnot grpmax-eligible	0.00161%	62,200
European (non-Finnish)	0.000511%	195,870

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.Pro192Leu
Coding: c.575C>T
MANE Select: NM_020919
dbSNP: rs778003334
Type: single nucleotide variant
Location: chr2:201761419 (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.Pro192= Likely benign ★ 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-pro192leu (accessed [today's date]).

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