Is ALS2 p.Tyr1398= (c.4194C>T) pathogenic?

ALS2 p.Tyr1398= (c.4194C>T) is classified Conflicting classifications of pathogenicity in ALS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-31). Rare (popmax 0.131%, mid); Associated with hereditary spastic paraplegia.

What condition is associated with ALS2 p.Tyr1398= (c.4194C>T)?

ALS2 p.Tyr1398= (c.4194C>T) is associated with hereditary spastic paraplegia, infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 p.Tyr1398= (c.4194C>T) in the general population?

ALS2 p.Tyr1398= (c.4194C>T) is rare (popmax 0.131%, mid) (gnomAD).

ALS2 p.Tyr1398=

c.4194C>T · rs764925739 · VCV1090663

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.131%, mid)

Conditions

hereditary spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.8	GERP -2.9
Overall
CADD	0.732	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.131% Middle Eastern · 8/6,084 alleles

Filtering AF 0.0654% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0477%

Overall 0.00415% 67/1,613,938 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.131%	761
African / African-American	0.036%	2,774
Admixed American	0.00834%	11,996
Remaining individualsnot grpmax-eligible	0.0064%	15,622
South Asian	0.0022%	45,544
European (non-Finnish)	0.00178%	56,189

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.Tyr1398=
Coding: c.4194C>T
MANE Select: NM_020919
dbSNP: rs764925739
Type: single nucleotide variant
Location: chr2:201709967 (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

hereditary spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: infantile-onset ascending hereditary spastic paralysis

Similar variants

ALS2 c.1640+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALS2 c.2580+2T>C Pathogenic ★★ same condition
ALS2 c.3703-2A>G 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.Arg1510Ter 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-tyr1398 (accessed [today's date]).

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