Is ATL1 p.Phe235= (c.705C>T) pathogenic?

ATL1 p.Phe235= (c.705C>T) is classified Benign in ATL1 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-14). Common (popmax 7.81%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hereditary spastic paraplegia 3A.

What condition is associated with ATL1 p.Phe235= (c.705C>T)?

ATL1 p.Phe235= (c.705C>T) is associated with hereditary spastic paraplegia 3A, neuropathy, hereditary sensory, type 1D, hereditary spastic paraplegia (ClinVar).

How is Autosomal dominant spastic paraplegia type 3 inherited?

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

ATL1 p.Phe235=

Q: How common is ATL1 p.Phe235= (c.705C>T) in the general population?

ATL1 p.Phe235= (c.705C>T) is common (popmax 7.81%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.705C>T · rs35044504 · VCV313300

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 7.81%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

hereditary spastic paraplegia 3A

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 1.3	GERP 0.85, phastCons 1
Overall
CADD	9.524	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.81% African / African-American · 5,843/74,830 alleles

Filtering AF 7.64% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.57%

Overall 0.419% 6,752/1,612,768 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.81%	13
Admixed American	0.656%	152
Remaining individualsnot grpmax-eligible	0.549%	182
Middle Eastern	0.31%	323
European (non-Finnish)	0.0127%	7,863
South Asian	0.00549%	18,208

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.Phe235=
Coding: c.705C>T
MANE Select: NM_015915
dbSNP: rs35044504
Type: single nucleotide variant
Location: chr14:50613333 (GRCh38)
Gene constraint: LOEUF 0.57 · pLI 0.36 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 86.49 · 14 PDB
Residue 235: an α-helix; the gb1/rhd3-type g domain

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

Also linked: neuropathy, hereditary sensory, type 1D hereditary spastic paraplegia

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.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.Gly409Cys 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-phe235 (accessed [today's date]).

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