Is UPF3B p.Ser25= (c.75C>T) pathogenic?

UPF3B p.Ser25= (c.75C>T) is classified Likely benign in UPF3B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-31). Ultra-rare (popmax 0.023%, mid); Associated with syndromic X-linked intellectual disability 14.

What condition is associated with UPF3B p.Ser25= (c.75C>T)?

UPF3B p.Ser25= (c.75C>T) is associated with syndromic X-linked intellectual disability 14 (ClinVar).

How common is UPF3B p.Ser25= (c.75C>T) in the general population?

UPF3B p.Ser25= (c.75C>T) is ultra-rare (popmax 0.023%, mid) (gnomAD).

UPF3B p.Ser25=

c.75C>T · rs780353084 · VCV753403

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.023%, mid)

Conditions

syndromic X-linked intellectual disability 14

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 2.5	GERP -2.8, phastCons 1
Overall
CADD	10.04	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.023% Middle Eastern · 1/4,354 alleles

Filtering AF 0.000164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000119%

Overall 0.00082% 9/1,098,171 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.023%	4,354
Remaining individualsnot grpmax-eligible	0.0042%	23,826
South Asian	0.00175%	57,054
European (non-Finnish)	0.000558%	179,112

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: UPF3B
Protein: p.Ser25=
Coding: c.75C>T
MANE Select: NM_080632
dbSNP: rs780353084
Type: single nucleotide variant
Location: chrX:119852854 (GRCh38)
Structure: AlphaFold pLDDT 67.35 · 3 PDB
Residue 25: the 'disordered' region

Full UPF3B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

syndromic X-linked intellectual disability 14 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

UPF3B p.Arg13Ter Likely pathogenic ★★ same condition
UPF3B p.Arg354Ter Likely pathogenic ★★ same condition
UPF3B p.Arg229Lys Uncertain significance ★★ ⚠ same condition
UPF3B p.Arg255Gly Uncertain significance ★★ same condition
UPF3B p.Arg259Lys Uncertain significance ★★ ⚠ same condition
UPF3B p.Arg313Gly Uncertain significance ★★ ⚠ same condition
UPF3B p.Arg350Gln Uncertain significance ★★ ⚠ same condition
UPF3B p.Arg368Trp 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/upf3b-p-ser25 (accessed [today's date]).

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