Is CTU2 p.Gln416Arg (c.1247A>G) pathogenic?

CTU2 p.Gln416Arg (c.1247A>G) is classified Benign in CTU2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0655); Common (popmax 62.7%, eas) — too common for a highly-penetrant pathogenic allele; Associated with microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome.

What do computational predictors say about CTU2 p.Gln416Arg (c.1247A>G)?

AlphaMissense predicts likely benign (score 0.0655) — an in-silico prediction, not a clinical call.

CTU2 p.Gln416Arg

Q: What condition is associated with CTU2 p.Gln416Arg (c.1247A>G)?

CTU2 p.Gln416Arg (c.1247A>G) is associated with microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (ClinVar).

Q: How common is CTU2 p.Gln416Arg (c.1247A>G) in the general population?

CTU2 p.Gln416Arg (c.1247A>G) is common (popmax 62.7%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1247A>G · rs8059048 · VCV1220852

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0655 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 62.7%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0655	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -5.36	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.91	acceptor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.21	GERP -1.8, phastCons 0.009
Regional constraint	o/e 1.61	unconstrained · MANE · 8,717 bp · p 1.9e-57 · regional, not allelic
Overall
CADD	7.619	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 62.7% East Asian · 28,123/44,828 alleles

Filtering AF 62.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 61.9%

Overall 21.3% 343,315/1,612,336 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	62.7%	2
Admixed American	40.5%	2
Finnishnot grpmax-eligible	26.3%	4
South Asian	23.8%	4
Ashkenazi Jewishnot grpmax-eligible	22.9%	4
Remaining individualsnot grpmax-eligible	22.8%	4
Middle Eastern	21.1%	5
African / African-American	18.7%	5
European (non-Finnish)	18.3%	5
Amishnot grpmax-eligible	13.7%	7

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.Gln416Arg
Coding: c.1247A>G
MANE Select: NM_001012759
dbSNP: rs8059048
Type: single nucleotide variant
Location: chr16:88714632 (GRCh38)
Gene constraint: LOEUF 1.535 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.27
Residue 416: a UniProt-annotated variant site (in)

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.Gln416Ter 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 c.1006-26A>G Benign ★★ same condition
CTU2 c.1201+29C>G Benign ★★ same condition
CTU2 c.1420-37A>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-gln416arg (accessed [today's date]).

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