Is ALS2 p.Pro550Leu (c.1649C>T) pathogenic?

ALS2 p.Pro550Leu (c.1649C>T) is classified Likely pathogenic in ALS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-14). AlphaMissense: likely pathogenic (0.9655); Very rare (popmax 0.00223%, eas); Associated with amyotrophic lateral sclerosis type 2, juvenile.

What condition is associated with ALS2 p.Pro550Leu (c.1649C>T)?

ALS2 p.Pro550Leu (c.1649C>T) is associated with amyotrophic lateral sclerosis type 2, juvenile (ClinVar).

How common is ALS2 p.Pro550Leu (c.1649C>T) in the general population?

ALS2 p.Pro550Leu (c.1649C>T) is very rare (popmax 0.00223%, eas) (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.Pro550Leu (c.1649C>T)?

AlphaMissense predicts likely pathogenic (score 0.9655) — an in-silico prediction, not a clinical call.

ALS2 p.Pro550Leu

c.1649C>T · rs2106071765 · VCV1339519

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9655 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis type 2, juvenile

Computational evidence

Protein change
AlphaMissense	0.9655	likely pathogenic ✓ concordant with ClinVar
REVEL	0.939	strongly pathogenic-leaning
SaProt	LLR -12.31	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 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 56 kb · p 7.1e-07 · regional, not allelic
Overall
CADD	32.0	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 0.00223% East Asian · 1/44,864 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,482 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,864
European (non-Finnish)	0.00017%	589,863

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.Pro550Leu
Coding: c.1649C>T
MANE Select: NM_020919
dbSNP: rs2106071765
Type: single nucleotide variant
Location: chr2:201753234 (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

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

ALS2 p.Pro550= Likely benign ★ same residue
ALS2 c.2580+2T>C 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
ALS2 p.Arg1461Ter Pathogenic ★★ same condition
ALS2 p.Arg201Ter 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-pro550leu (accessed [today's date]).

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