Is ALS2 p.Leu1213Trp (c.3638T>G) pathogenic?

ALS2 p.Leu1213Trp (c.3638T>G) is classified Uncertain significance in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). AlphaMissense: likely pathogenic (0.9868); Very rare (popmax 6.85e-05%); Associated with Inborn genetic diseases.

What condition is associated with ALS2 p.Leu1213Trp (c.3638T>G)?

ALS2 p.Leu1213Trp (c.3638T>G) is associated with Inborn genetic diseases (ClinVar).

How common is ALS2 p.Leu1213Trp (c.3638T>G) in the general population?

ALS2 p.Leu1213Trp (c.3638T>G) is very rare (popmax 6.85e-05%) (gnomAD).

What do computational predictors say about ALS2 p.Leu1213Trp (c.3638T>G)?

AlphaMissense predicts likely pathogenic (score 0.9868) — an in-silico prediction, not a clinical call.

ALS2 p.Leu1213Trp

c.3638T>G · rs1690914791 · VCV3114144

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9868 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.85e-05%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9868	likely pathogenic · top 8% in ALS2
REVEL	0.634	indeterminate
SaProt	LLR -11.54	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 56 kb · p 7.1e-07 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.85e-05%

Overall 6.85e-05% 1/1,460,906 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.Leu1213Trp
Coding: c.3638T>G
MANE Select: NM_020919
dbSNP: rs1690914791
Type: single nucleotide variant
Location: chr2:201723107 (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.Leu1213= Likely benign ★ 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
ALS2 p.Arg1405Cys 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-leu1213trp (accessed [today's date]).

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