Is UBQLN2 p.Phe65= (c.195C>T) pathogenic?

UBQLN2 p.Phe65= (c.195C>T) is classified Likely benign in UBQLN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-14). Ultra-rare (popmax 0.0687%, mid); Associated with amyotrophic lateral sclerosis type 15.

What condition is associated with UBQLN2 p.Phe65= (c.195C>T)?

UBQLN2 p.Phe65= (c.195C>T) is associated with amyotrophic lateral sclerosis type 15 (ClinVar).

How common is UBQLN2 p.Phe65= (c.195C>T) in the general population?

UBQLN2 p.Phe65= (c.195C>T) is ultra-rare (popmax 0.0687%, mid) (gnomAD).

UBQLN2 p.Phe65=

c.195C>T · rs754649110 · VCV1988072

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0687%, mid)

Conditions

amyotrophic lateral sclerosis type 15

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 4.1	phastCons 1
Overall
CADD	13.79	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0687% Middle Eastern · 3/4,368 alleles

Filtering AF 0.0186% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00993%

Overall 0.00191% 23/1,204,626 alleles · ultra-rare exomes 21/1,092,224 · genomes 2/112,402 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0687%	1,456
Remaining individualsnot grpmax-eligible	0.00422%	23,708
European (non-Finnish)	0.00179%	55,745
South Asian	0.00179%	55,840
African / African-American	0.00175%	57,261

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: UBQLN2
Protein: p.Phe65=
Coding: c.195C>T
MANE Select: NM_013444
dbSNP: rs754649110
Type: single nucleotide variant
Location: chrX:56564068 (GRCh38)
Structure: AlphaFold pLDDT 62.24 · 4 PDB
Residue 65: the ubiquitin-like domain; an α-helix

Full UBQLN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

amyotrophic lateral sclerosis type 15 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

UBQLN2 p.Pro497His Pathogenic ★★ same condition
UBQLN2 p.Ala26Ser Uncertain significance ★★ ⚠ same condition
UBQLN2 p.Ala282Thr Uncertain significance ★★ ⚠ same condition
UBQLN2 p.Ala361Thr Uncertain significance ★★ ⚠ same condition
UBQLN2 p.Ala523Val Uncertain significance ★★ ⚠ same condition
UBQLN2 p.Arg270Cys Uncertain significance ★★ ⚠ same condition
UBQLN2 p.Asn122Asp Uncertain significance ★★ ⚠ same condition
UBQLN2 p.Asp85His Uncertain significance ★★ ⚠ 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/ubqln2-p-phe65 (accessed [today's date]).

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