Is ALS2 p.Pro1603Leu (c.4808C>T) pathogenic?

ALS2 p.Pro1603Leu (c.4808C>T) is classified Likely pathogenic in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-31). AlphaMissense: likely pathogenic (0.9901); Very rare (popmax 8.47e-05%, nfe); Associated with amyotrophic lateral sclerosis type 2, juvenile.

What condition is associated with ALS2 p.Pro1603Leu (c.4808C>T)?

ALS2 p.Pro1603Leu (c.4808C>T) is associated with amyotrophic lateral sclerosis type 2, juvenile (ClinVar).

How common is ALS2 p.Pro1603Leu (c.4808C>T) in the general population?

ALS2 p.Pro1603Leu (c.4808C>T) is very rare (popmax 8.47e-05%, nfe) (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.Pro1603Leu (c.4808C>T)?

AlphaMissense predicts likely pathogenic (score 0.9901) — an in-silico prediction, not a clinical call.

ALS2 p.Pro1603Leu

c.4808C>T · rs1689580631 · VCV873269

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9901 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis type 2, juvenile

Computational evidence

Protein change
AlphaMissense	0.9901	likely pathogenic ✓ concordant with ClinVar · top 7% in ALS2
REVEL	0.73	pathogenic-leaning
SaProt	LLR -11.64	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 0.87	unconstrained · MANE · 56 kb · p 7.1e-07 · regional, not allelic
Overall
CADD	30.0	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 8.47e-05% European (non-Finnish) · 1/1,179,996 alleles

Overall 0.000657% 1/152,094 alleles · very rare

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.Pro1603Leu
Coding: c.4808C>T
MANE Select: NM_020919
dbSNP: rs1689580631
Type: single nucleotide variant
Location: chr2:201704484 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.69
Residue 1603: the vps9 domain

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

For Juvenile amyotrophic lateral sclerosis (Orphanet):

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

Similar variants

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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
ALS2 p.Arg201Ter Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Arg921Ter 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-pro1603leu (accessed [today's date]).

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