Is ALS2 p.Leu48Val (c.142C>G) pathogenic?

ALS2 p.Leu48Val (c.142C>G) is classified Likely pathogenic in ALS2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-07-01). AlphaMissense: likely benign (0.1027); Absent from gnomAD v4.1; Associated with amyotrophic lateral sclerosis.

What condition is associated with ALS2 p.Leu48Val (c.142C>G)?

ALS2 p.Leu48Val (c.142C>G) is associated with amyotrophic lateral sclerosis (ClinVar).

How common is ALS2 p.Leu48Val (c.142C>G) in the general population?

ALS2 p.Leu48Val (c.142C>G) is absent from gnomAD v4.1 (gnomAD).

How is Amyotrophic lateral sclerosis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ALS2 p.Leu48Val (c.142C>G)?

AlphaMissense predicts likely benign (score 0.1027) — an in-silico prediction, not a clinical call.

ALS2 p.Leu48Val

c.142C>G · rs2106102324 · VCV1699990

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1027 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis

Computational evidence

Protein change
AlphaMissense	0.1027	likely benign ⚠ discordant with ClinVar
REVEL	0.687	pathogenic-leaning
SaProt	LLR -5.27	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0064 · regional, not allelic
Overall
CADD	24.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ALS2
Protein: p.Leu48Val
Coding: c.142C>G
MANE Select: NM_020919
dbSNP: rs2106102324
Type: single nucleotide variant
Location: chr2:201767262 (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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Amyotrophic lateral sclerosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

ALS2 p.Leu48Phe Uncertain significance ★ ⚠ same residue
ALS2 p.Leu48= Likely benign ★ same residue
ALS2 c.3624+1G>A Pathogenic ★ same condition
ALS2 p.Arg741Ter Pathogenic ★ same condition
ALS2 p.Gly1069Glu Conflicting classifications of pathogenicity ★ ⚠ same condition
ALS2 c.1640+1G>A Pathogenic/Likely pathogenic ★★ same type
ALS2 c.2580+2T>C Pathogenic ★★ same type
ALS2 c.3703-2A>G Pathogenic/Likely pathogenic ★★ same type

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-leu48val (accessed [today's date]).

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