Is ATL1 p.Arg495Gln (c.1484G>A) pathogenic?

ATL1 p.Arg495Gln (c.1484G>A) is classified Conflicting classifications of pathogenicity in ATL1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-08-13). AlphaMissense: likely pathogenic (0.933); Very rare (popmax 0.0011%, sas); Associated with hereditary spastic paraplegia 3A.

What condition is associated with ATL1 p.Arg495Gln (c.1484G>A)?

ATL1 p.Arg495Gln (c.1484G>A) is associated with hereditary spastic paraplegia 3A (ClinVar).

How common is ATL1 p.Arg495Gln (c.1484G>A) in the general population?

ATL1 p.Arg495Gln (c.1484G>A) is very rare (popmax 0.0011%, sas) (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.Arg495Gln (c.1484G>A)?

AlphaMissense predicts likely pathogenic (score 0.933) — an in-silico prediction, not a clinical call.

ATL1 p.Arg495Gln

c.1484G>A · rs985551666 · VCV2179806

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.933 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 3A

Computational evidence

Protein change
AlphaMissense	0.933	likely pathogenic
REVEL	0.835	moderately pathogenic-leaning
SaProt	LLR -11.17	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 9.9	GERP 0.16, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 9,131 bp · p 2.1e-07 · regional, not allelic
Overall
CADD	29.4	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

Grpmax group 0.0011% South Asian · 1/91,076 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,944 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,076
European (non-Finnish)	0.000169%	590,012

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: ATL1
Protein: p.Arg495Gln
Coding: c.1484G>A
MANE Select: NM_015915
dbSNP: rs985551666
Type: single nucleotide variant
Location: chr14:50628395 (GRCh38)
Gene constraint: LOEUF 0.57 · pLI 0.36 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 86.49 · 14 PDB
Residue 495: a UniProt-annotated variant site (in spg3; changed endoplasmic reticulum tubular network organization; endoplasmic reticulum and golgi morphology are affected)

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.Arg495Trp Pathogenic/Likely pathogenic ★★ same residue
ATL1 p.Arg495= Likely benign ★ 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

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-arg495gln (accessed [today's date]).

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