Is DNM1L p.Pro85Ala (c.253C>G) pathogenic?

DNM1L p.Pro85Ala (c.253C>G) is classified Uncertain significance in DNM1L (ClinVar, Single submitter, 1 submitter; last evaluated 2019-01-01). Very rare (popmax 0.00017%, nfe); Associated with hereditary spastic paraplegia 8.

What condition is associated with DNM1L p.Pro85Ala (c.253C>G)?

DNM1L p.Pro85Ala (c.253C>G) is associated with hereditary spastic paraplegia 8 (ClinVar).

How common is DNM1L p.Pro85Ala (c.253C>G) in the general population?

DNM1L p.Pro85Ala (c.253C>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Autosomal dominant spastic paraplegia type 8 inherited?

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

DNM1L p.Pro85Ala

c.253C>G · rs762401850 · VCV634573

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

hereditary spastic paraplegia 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.44	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 19 kb · p 1.9e-12 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,508 alleles

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

Overall 0.000125% 2/1,597,696 alleles · very rare

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: DNM1L
Protein: p.Pro85Ala
Coding: c.253C>G
MANE Select: NM_012062 · reported on NM_001278464
dbSNP: rs762401850
Type: single nucleotide variant
Location: chr12:32705827 (GRCh38)
Gene constraint: LOEUF 0.506 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 77.09 · 11 PDB
Residue 85: the dynamin-type g domain

Full DNM1L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant spastic paraplegia type 8 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

DNM1L p.Val85Leu Uncertain significance ★ ⚠ same residue
DNM1L p.Pro85fs Likely pathogenic ★ same residue
DNM1L c.1596+2T>A Likely pathogenic ★★ same type
DNM1L c.1674+1G>A Pathogenic/Likely pathogenic ★★ same type
DNM1L p.Arg403Cys Pathogenic ★★ same type
DNM1L p.Arg530Ter Pathogenic/Likely pathogenic ★★ same type
DNM1L p.Asp146Asn Pathogenic/Likely pathogenic ★★ same type
DNM1L p.Cys431Tyr Pathogenic ★★ same type

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/dnm1l-p-pro85ala (accessed [today's date]).

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