Is ATL1 p.Arg198Ser (c.594A>C) pathogenic?

ATL1 p.Arg198Ser (c.594A>C) is classified Likely pathogenic in ATL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-01). AlphaMissense: likely pathogenic (0.9965); Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia 3A.

What condition is associated with ATL1 p.Arg198Ser (c.594A>C)?

ATL1 p.Arg198Ser (c.594A>C) is associated with hereditary spastic paraplegia 3A (ClinVar).

How common is ATL1 p.Arg198Ser (c.594A>C) in the general population?

ATL1 p.Arg198Ser (c.594A>C) is absent from gnomAD v4.1 (gnomAD).

How is Autosomal dominant spastic paraplegia type 3 inherited?

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

What do computational predictors say about ATL1 p.Arg198Ser (c.594A>C)?

AlphaMissense predicts likely pathogenic (score 0.9965) — an in-silico prediction, not a clinical call.

ATL1 p.Arg198Ser

c.594A>C · rs1555364247 · VCV471250

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9965 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary spastic paraplegia 3A

Computational evidence

Protein change
AlphaMissense	0.9965	likely pathogenic ✓ concordant with ClinVar
REVEL	0.618	indeterminate
SaProt	LLR -12.68	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 0.88	GERP -1.9, phastCons 0.37
Regional constraint	o/e 0.37	unconstrained · MANE · 23 kb · p 7.5e-16 · regional, not allelic
Overall
CADD	22.3	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: ATL1
Protein: p.Arg198Ser
Coding: c.594A>C
MANE Select: NM_015915
dbSNP: rs1555364247
Type: single nucleotide variant
Location: chr14:50595596 (GRCh38)
Gene constraint: LOEUF 0.57 · pLI 0.36 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 86.49 · 14 PDB
Residue 198: the gb1/rhd3-type g domain; an α-helix

Full ATL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 3A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant spastic paraplegia type 3 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Childhood
Prevalence: 1-9 / 1 000 000 (Portugal)

Similar variants

ATL1 p.Arg198Gly Likely pathogenic ★ same residue
ATL1 p.Arg217Gln Pathogenic/Likely pathogenic ★★ same condition
ATL1 p.Arg239Cys Pathogenic/Likely pathogenic ★★ same condition
ATL1 p.Arg239His Likely pathogenic ★★ same condition
ATL1 p.Arg403Pro Likely pathogenic ★★ same condition
ATL1 p.Arg415Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
ATL1 p.Arg416Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
ATL1 p.Arg495Trp 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/atl1-p-arg198ser (accessed [today's date]).

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