Is ALS2 p.Asp595Tyr (c.1783G>T) pathogenic?

ALS2 p.Asp595Tyr (c.1783G>T) is classified Uncertain significance in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.1582); Absent from gnomAD v4.1; Associated with amyotrophic lateral sclerosis type 2, juvenile.

What condition is associated with ALS2 p.Asp595Tyr (c.1783G>T)?

ALS2 p.Asp595Tyr (c.1783G>T) is associated with amyotrophic lateral sclerosis type 2, juvenile (ClinVar).

How common is ALS2 p.Asp595Tyr (c.1783G>T) in the general population?

ALS2 p.Asp595Tyr (c.1783G>T) is absent from gnomAD v4.1 (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.Asp595Tyr (c.1783G>T)?

AlphaMissense predicts likely benign (score 0.1582) — an in-silico prediction, not a clinical call.

ALS2 p.Asp595Tyr

c.1783G>T · rs199603159 · VCV898198

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1582 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

amyotrophic lateral sclerosis type 2, juvenile

Computational evidence

Protein change
AlphaMissense	0.1582	likely benign
REVEL	0.455	indeterminate
SaProt	LLR -8.75	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 56 kb · p 7.1e-07 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

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.Asp595Tyr
Coding: c.1783G>T
MANE Select: NM_020919
dbSNP: rs199603159
Type: single nucleotide variant
Location: chr2:201749744 (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.Asp595Asn Uncertain significance ★★ ⚠ 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-asp595tyr (accessed [today's date]).

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