Is ALS2 p.Leu48Phe (c.142C>T) pathogenic?

ALS2 p.Leu48Phe (c.142C>T) is classified Uncertain significance in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-07). AlphaMissense: likely benign (0.232); Very rare (popmax 6.84e-05%); Associated with Inborn genetic diseases.

What condition is associated with ALS2 p.Leu48Phe (c.142C>T)?

ALS2 p.Leu48Phe (c.142C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ALS2 p.Leu48Phe (c.142C>T) in the general population?

ALS2 p.Leu48Phe (c.142C>T) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about ALS2 p.Leu48Phe (c.142C>T)?

AlphaMissense predicts likely benign (score 0.232) — an in-silico prediction, not a clinical call.

ALS2 p.Leu48Phe

c.142C>T · rs2106102324 · VCV2482052

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.232 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.232	likely benign
REVEL	0.762	pathogenic-leaning
SaProt	LLR -5.58	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	24.7	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 6.84e-05%

Overall 6.84e-05% 1/1,461,876 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.Leu48Phe
Coding: c.142C>T
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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ALS2 p.Leu48= Likely benign ★ same residue
ALS2 p.Leu48Val Likely pathogenic ⚠ same residue
ALS2 p.Arg1139Ter Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Ala333Ser Uncertain significance ★★ ⚠ same condition
ALS2 p.Ala377Thr Uncertain significance ★★ ⚠ same condition
ALS2 p.Ala402Thr Uncertain significance ★★ ⚠ same condition
ALS2 p.Arg1329Trp Uncertain significance ★★ ⚠ same condition
ALS2 p.Arg1330His Uncertain significance ★★ ⚠ 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-leu48phe (accessed [today's date]).

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