# NM_015915.5(ATL1):c.705C>T (p.Phe235=)

https://sugi.bio/variant/atl1-p-phe235

## Summary

**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.

**At a glance:** Benign · review: Multiple submitters · rsID rs35044504 · 11 submitters · 3 linked conditions · common (popmax 7.81%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the ATL1 gene that is classified as benign — not considered disease-causing, submitted by 11 submitters, and is linked to hereditary spastic paraplegia 3A.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adult, Childhood |
| Prevalence | 1-9 / 1 000 000 (Portugal) |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ATL1 is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Autosomal dominant spastic paraplegia type 3** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Lower limb spasticity — Very frequent (99-80%)
- Lower limb hyperreflexia — Very frequent (99-80%)
- Babinski sign — Very frequent (99-80%)
- Distal lower limb muscle weakness — Very frequent (99-80%)
- Gait disturbance — Frequent (79-30%)
- Spastic gait — Frequent (79-30%)
- Distal lower limb amyotrophy — Frequent (79-30%)
- Ankle clonus — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005041/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ATL1](https://sugi.bio/atlas/gene/ATL1/) |
| Protein change (HGVS p.) | p.Phe235= |
| Coding change (HGVS c.) | c.705C>T |
| MANE Select transcript | [NM_015915](https://www.ncbi.nlm.nih.gov/nuccore/NM_015915) |
| dbSNP | [rs35044504](https://www.ncbi.nlm.nih.gov/snp/rs35044504/) |
| Variant type | single nucleotide variant |
| Location | chr14:50613333-50613333 (GRCh38) |
| ClinVar | [VCV313300](https://www.ncbi.nlm.nih.gov/clinvar/variation/313300/) |

**All HGVS expressions:** `LRG_360:g.85252C>T`, `LRG_360t1:c.705C>T`, `LRG_360t2:c.705C>T`, `NC_000014.8:g.51080051C>T`, `NC_000014.9:g.50613333C>T`, `NG_009028.1:g.85252C>T`, `NM_001127713.1:c.705C>T`, `NM_015915.5:c.705C>T`, `NM_181598.4:c.705C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 7.81%, afr) — too common for a highly-penetrant pathogenic allele.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.327, GERP 0.855, phastCons 1 — weakly conserved position
- CADD: **PHRED 9.524**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **7.81%** (afr) · FAF95 7.64% · FAF99 7.57% · 5,843/74,830 in the highest group · 6,752/1,612,768 alleles overall — common (popmax 7.81%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 7.81% | 13 |
| Admixed American | 0.656% | 152 |
| Remaining individuals (not grpmax-eligible) | 0.549% | 182 |
| Middle Eastern | 0.31% | 323 |
| European (non-Finnish) | 0.0127% | 7,863 |
| South Asian | 0.00549% | 18,208 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ATL1** population constraint: LOEUF 0.57, pLI 0.35895, missense-Z 3.8464; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **neuropathy, hereditary sensory, type 1D** — Definitive (AD)

## Protein context {#protein}

Residue **235** lies in an α-helix; the gb1/rhd3-type g domain.

AlphaFold model confidence (whole protein): pLDDT 86.49, 65% of residues very-high.

**14 experimental structure(s)** (PDB): [3Q5D](https://www.rcsb.org/structure/3Q5D), [3Q5E](https://www.rcsb.org/structure/3Q5E), [3QNU](https://www.rcsb.org/structure/3QNU), [3QOF](https://www.rcsb.org/structure/3QOF), [4IDN](https://www.rcsb.org/structure/4IDN), [4IDO](https://www.rcsb.org/structure/4IDO) — incl. mutant structure 6B9D.

## What this gene does {#gene-function}

*Describes the biological roles of ATL1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ATL1's established molecular role includes identical protein binding. p.Phe235= falls in the gb1/rhd3-type g domain.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** identical protein binding, GTPase-dependent fusogenic activity.

**Biological process:** endoplasmic reticulum membrane fusion, endoplasmic reticulum tubular network membrane organization.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-14.

**Submitter consensus:** conflicting (11 Benign, 1 benign).

**Submission history:** 12 submissions (2015–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-10-27 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-14 |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Benign | criteria provided, single submitter | clinical testing | 2020-04-01 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-12-05 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2024-10-15 |
| Athena Diagnostics | benign | criteria provided, single submitter | clinical testing | 2024-10-31 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2016-03-07 |

## Associated conditions {#conditions}

[hereditary spastic paraplegia 3A](https://sugi.bio/atlas/disease/hereditary-spastic-paraplegia-3a/), [neuropathy, hereditary sensory, type 1D](https://sugi.bio/atlas/disease/neuropathy-hereditary-sensory-type-1d/), [hereditary spastic paraplegia](https://sugi.bio/atlas/disease/hereditary-spastic-paraplegia/).

**Reported phenotype names (ClinVar):** Hereditary spastic paraplegia 3A, not specified, not provided, Hereditary spastic paraplegia, Neuropathy, hereditary sensory, type 1D, SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT, FAMILIAL SPASTIC PARAPLEGIA, AUTOSOMAL DOMINANT, 1, SPG3, STRUMPELL DISEASE, Spastic Paraplegia 3A.

## Similar variants {#similar}

Related ATL1 variant pages (same residue, condition, or type): [ATL1 p.Arg217Gln](/variant/atl1-p-arg217gln), [ATL1 p.Arg239Cys](/variant/atl1-p-arg239cys), [ATL1 p.Arg239His](/variant/atl1-p-arg239his), [ATL1 p.Arg403Pro](/variant/atl1-p-arg403pro), [ATL1 p.Arg415Trp](/variant/atl1-p-arg415trp), [ATL1 p.Arg416Cys](/variant/atl1-p-arg416cys), [ATL1 p.Arg495Trp](/variant/atl1-p-arg495trp), [ATL1 p.Gly409Cys](/variant/atl1-p-gly409cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 313300). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*