Is USP26 p.Phe42Ser (c.125T>C) pathogenic?

USP26 p.Phe42Ser (c.125T>C) is classified Uncertain significance in USP26 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.6646); Ultra-rare (popmax 0.0148%, eas); Associated with oligospermia.

What condition is associated with USP26 p.Phe42Ser (c.125T>C)?

USP26 p.Phe42Ser (c.125T>C) is associated with oligospermia (ClinVar).

How common is USP26 p.Phe42Ser (c.125T>C) in the general population?

USP26 p.Phe42Ser (c.125T>C) is ultra-rare (popmax 0.0148%, eas) (gnomAD).

What do computational predictors say about USP26 p.Phe42Ser (c.125T>C)?

AlphaMissense predicts likely pathogenic (score 0.6646) — an in-silico prediction, not a clinical call.

USP26 p.Phe42Ser

c.125T>C · VCV3239641

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6646 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0148%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

oligospermia

Computational evidence

Protein change
AlphaMissense	0.6646	likely pathogenic · top 7% in USP26
REVEL	0.235	benign-leaning
SaProt	LLR -11.64	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.5	GERP 1.4, phastCons 0.17
Regional constraint	o/e 1.04	unconstrained · MANE · 2,513 bp · p 0.29 · regional, not allelic
Overall
CADD	16.91	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 0.0148% East Asian · 5/33,784 alleles

Filtering AF 0.00581% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00373%

Overall 0.000413% 5/1,209,770 alleles · ultra-rare exomes 4/1,097,591 · genomes 1/112,179 · joint denominator

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: USP26
Protein: p.Phe42Ser
Coding: c.125T>C
MANE Select: NM_031907
Type: single nucleotide variant
Location: chrX:133028096 (GRCh38)
Structure: AlphaFold pLDDT 60.28

Full USP26 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

oligospermia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

USP26 p.Arg7His Likely benign ★★ same type
USP26 p.Asp274= Benign ★★ same type
USP26 p.Glu192= Benign ★★ same type
USP26 p.Met579Ile Benign ★★ same type
USP26 p.Thr659Met Likely benign ★★ same type
USP26 p.Ala25Glu Uncertain significance ★ ⚠ same type
USP26 p.Ala450Thr Uncertain significance ★ ⚠ same type
USP26 p.Ala868Asp Uncertain significance ★ ⚠ 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/usp26-p-phe42ser (accessed [today's date]).

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