Is ATL1 p.Leu357Ser (c.1070T>C) pathogenic?

ATL1 p.Leu357Ser (c.1070T>C) is classified Uncertain significance in ATL1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-10). AlphaMissense: likely pathogenic (0.9988); Absent from gnomAD v4.1; Associated with ATL1-related disorder.

What condition is associated with ATL1 p.Leu357Ser (c.1070T>C)?

ATL1 p.Leu357Ser (c.1070T>C) is associated with ATL1-related disorder, hereditary spastic paraplegia 3A (ClinVar).

How common is ATL1 p.Leu357Ser (c.1070T>C) in the general population?

ATL1 p.Leu357Ser (c.1070T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ATL1 p.Leu357Ser (c.1070T>C)?

AlphaMissense predicts likely pathogenic (score 0.9988) — an in-silico prediction, not a clinical call.

ATL1 p.Leu357Ser

c.1070T>C · rs2504564196 · VCV1714113

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9988 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ATL1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9988	likely pathogenic · top 9% in ATL1
REVEL	0.873	moderately pathogenic-leaning
SaProt	LLR -14.29	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.05	constrained · MANE · 1,323 bp · p 4.8e-05 · regional, not allelic
Overall
CADD	29.1	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

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.Leu357Ser
Coding: c.1070T>C
MANE Select: NM_015915
dbSNP: rs2504564196
Type: single nucleotide variant
Location: chr14:50623199 (GRCh38)
Gene constraint: LOEUF 0.57 · pLI 0.36 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 86.49 · 14 PDB
Residue 357: an α-helix; the '3hb (three-helix bundle) domain' region

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

Disease context

ATL1-related disorder

Also linked: hereditary spastic paraplegia 3A

Similar variants

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
ATL1 p.Arg501Ter 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-leu357ser (accessed [today's date]).

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