Is UBAP1 p.Gln422Arg (c.1265A>G) pathogenic?

UBAP1 p.Gln422Arg (c.1265A>G) is classified Likely pathogenic in UBAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-01). AlphaMissense: likely benign (0.238); Very rare (popmax 0.0011%, sas); Associated with spastic paraplegia 80, autosomal dominant.

What condition is associated with UBAP1 p.Gln422Arg (c.1265A>G)?

UBAP1 p.Gln422Arg (c.1265A>G) is associated with spastic paraplegia 80, autosomal dominant (ClinVar).

How common is UBAP1 p.Gln422Arg (c.1265A>G) in the general population?

UBAP1 p.Gln422Arg (c.1265A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Autosomal dominant spastic paraplegia type 80 inherited?

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

What do computational predictors say about UBAP1 p.Gln422Arg (c.1265A>G)?

AlphaMissense predicts likely benign (score 0.238) — an in-silico prediction, not a clinical call.

UBAP1 p.Gln422Arg

c.1265A>G · rs1227081826 · VCV1679276

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.238 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

spastic paraplegia 80, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.238	likely benign ⚠ discordant with ClinVar
REVEL	0.41	indeterminate
SaProt	LLR -5.97	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 9,962 bp · p 0.0098 · regional, not allelic
Overall
CADD	33.0	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 · 1/91,066 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000929% 15/1,613,818 alleles · very rare exomes 13/1,461,582 · genomes 2/152,236 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,227
South Asiangrpmax	0.0011%	91,066
European (non-Finnish)	0.00102%	98,332

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: UBAP1
Protein: p.Gln422Arg
Coding: c.1265A>G
MANE Select: NM_016525
dbSNP: rs1227081826
Type: single nucleotide variant
Location: chr9:34249960 (GRCh38)
Gene constraint: LOEUF 0.285 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.60 · 3 PDB
Residue 422: a UniProt-annotated variant site (in spg80); a UniProt-annotated variant site (in spg80; uncertain significance); the uba 1 domain; an α-helix

Full UBAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spastic paraplegia 80, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant spastic paraplegia type 80 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Childhood

Similar variants

UBAP1 c.-20C>T Likely pathogenic ★ same condition
UBAP1 p.Glu160Ter Likely pathogenic ★ same condition
UBAP1 p.Glu163Ter Likely pathogenic ★ same condition
UBAP1 p.Glu179Ter Pathogenic ★ same condition
UBAP1 p.Gly7Ter Likely pathogenic ★ same condition
UBAP1 p.Lys106Ter Pathogenic ★ same condition
UBAP1 p.Arg9Trp Conflicting classifications of pathogenicity ★ same condition
UBAP1 p.Glu418Lys Conflicting classifications of pathogenicity ★ ⚠ 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/ubap1-p-gln422arg (accessed [today's date]).

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