Is ATL1 p.Ile472Ser (c.1415T>G) pathogenic?

ATL1 p.Ile472Ser (c.1415T>G) is classified Uncertain significance in ATL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-05). AlphaMissense: ambiguous (0.4094); Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia 3A.

What condition is associated with ATL1 p.Ile472Ser (c.1415T>G)?

ATL1 p.Ile472Ser (c.1415T>G) is associated with hereditary spastic paraplegia 3A (ClinVar).

How common is ATL1 p.Ile472Ser (c.1415T>G) in the general population?

ATL1 p.Ile472Ser (c.1415T>G) 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.Ile472Ser (c.1415T>G)?

AlphaMissense predicts ambiguous (score 0.4094) — an in-silico prediction, not a clinical call.

ATL1 p.Ile472Ser

c.1415T>G · rs776586105 · VCV2044136

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4094 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary spastic paraplegia 3A

Computational evidence

Protein change
AlphaMissense	0.4094	ambiguous
REVEL	0.411	indeterminate
SaProt	LLR -9.67	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP -0.59, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 9,131 bp · p 2.1e-07 · regional, not allelic
Overall
CADD	20.1	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.Ile472Ser
Coding: c.1415T>G
MANE Select: NM_015915
dbSNP: rs776586105
Type: single nucleotide variant
Location: chr14:50628326 (GRCh38)
Gene constraint: LOEUF 0.57 · pLI 0.36 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 86.49 · 14 PDB

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.Ile472Val Uncertain significance ★★ ⚠ 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-ile472ser (accessed [today's date]).

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