Is CTU2 p.Ser294Ter (c.881C>A) pathogenic?

CTU2 p.Ser294Ter (c.881C>A) is classified Conflicting classifications of pathogenicity in CTU2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-15). Ultra-rare (popmax 0.032%, nfe); Associated with microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome.

How common is CTU2 p.Ser294Ter (c.881C>A) in the general population?

CTU2 p.Ser294Ter (c.881C>A) is ultra-rare (popmax 0.032%, nfe) (gnomAD).

CTU2 p.Ser294Ter

Q: What condition is associated with CTU2 p.Ser294Ter (c.881C>A)?

CTU2 p.Ser294Ter (c.881C>A) is associated with microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (ClinVar).

c.881C>A · rs201111272 · VCV2067774

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.032%, nfe)

Conditions

microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 15
Splicing
SpliceAI	Δ0.42	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 3.9	GERP 2.1, phastCons 1
Overall
CADD	54.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.032% European (non-Finnish) · 377/1,179,626 alleles

Filtering AF 0.0293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0282%

Overall 0.0247% 399/1,612,152 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.032%	3,129
Remaining individualsnot grpmax-eligible	0.0176%	5,679
Admixed American	0.0133%	7,498
Finnishnot grpmax-eligible	0.00319%	31,305
African / African-American	0.00133%	75,054

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: CTU2
Protein: p.Ser294Ter
Coding: c.881C>A
MANE Select: NM_001012759
dbSNP: rs201111272
Type: single nucleotide variant
Location: chr16:88713654 (GRCh38)
Gene constraint: LOEUF 1.535 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.27

Full CTU2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CTU2 p.Ser294= Likely benign ★ same residue
CTU2 c.1420-1G>A Likely pathogenic ★★ same condition
CTU2 c.282+5G>A Pathogenic ★★ same condition
CTU2 p.Gln243Ter Pathogenic/Likely pathogenic ★★ same condition
CTU2 p.Thr291= Pathogenic ★★ same condition
CTU2 p.Gln416Ter Uncertain significance ★★ same condition
CTU2 c.1006-26A>G Benign ★★ same condition
CTU2 c.1201+29C>G Benign ★★ 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/ctu2-p-ser294ter (accessed [today's date]).

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