Is CTU2 p.Arg67Trp (c.199C>T) pathogenic?

CTU2 p.Arg67Trp (c.199C>T) is classified Conflicting classifications of pathogenicity in CTU2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-05-28). AlphaMissense: ambiguous (0.5503); Ultra-rare (popmax 0.0164%, mid); Associated with microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome.

How common is CTU2 p.Arg67Trp (c.199C>T) in the general population?

CTU2 p.Arg67Trp (c.199C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CTU2 p.Arg67Trp (c.199C>T)?

AlphaMissense predicts ambiguous (score 0.5503) — an in-silico prediction, not a clinical call.

CTU2 p.Arg67Trp

Q: What condition is associated with CTU2 p.Arg67Trp (c.199C>T)?

CTU2 p.Arg67Trp (c.199C>T) is associated with microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (ClinVar).

c.199C>T · rs200836148 · VCV2215590

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5503 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.5503	ambiguous
REVEL	0.605	indeterminate
SaProt	LLR -9.93	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.62, phastCons 1
Regional constraint	o/e 1.61	unconstrained · MANE · 8,717 bp · p 1.9e-57 · regional, not allelic
Overall
CADD	28.9	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00186% 30/1,613,808 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0048%	20,828
African / African-American	0.00267%	37,462
European (non-Finnish)	0.00203%	49,167

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.Arg67Trp
Coding: c.199C>T
MANE Select: NM_001012759
dbSNP: rs200836148
Type: single nucleotide variant
Location: chr16:88709993 (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.Arg67Gln Uncertain significance ★★ ⚠ 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-arg67trp (accessed [today's date]).

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