Is CTU2 p.Cys444Ser (c.1331G>C) pathogenic?

CTU2 p.Cys444Ser (c.1331G>C) is classified Uncertain significance in CTU2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-28). AlphaMissense: likely benign (0.1225); Ultra-rare (popmax 0.0659%, mid).

How common is CTU2 p.Cys444Ser (c.1331G>C) in the general population?

CTU2 p.Cys444Ser (c.1331G>C) is ultra-rare (popmax 0.0659%, mid) (gnomAD).

What do computational predictors say about CTU2 p.Cys444Ser (c.1331G>C)?

AlphaMissense predicts likely benign (score 0.1225) — an in-silico prediction, not a clinical call.

CTU2 p.Cys444Ser

c.1331G>C · VCV4657642

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1225 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0659%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1225	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -4.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.4	GERP 1.4, phastCons 1
Regional constraint	o/e 1.61	unconstrained · MANE · 8,717 bp · p 1.9e-57 · regional, not allelic
Overall
CADD	14.01	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0659% Middle Eastern · 4/6,070 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00137% 22/1,608,834 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0659%	1,517
South Asian	0.00661%	15,130
Remaining individualsnot grpmax-eligible	0.00642%	15,564
European (non-Finnish)	0.000679%	147,249

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.Cys444Ser
Coding: c.1331G>C
MANE Select: NM_001012759
Type: single nucleotide variant
Location: chr16:88714716 (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

Similar variants

CTU2 p.Cys444= Benign ★★ same residue
CTU2 c.1420-1G>A Likely pathogenic ★★ same type
CTU2 c.282+5G>A Pathogenic ★★ same type
CTU2 p.Gln243Ter Pathogenic/Likely pathogenic ★★ same type
CTU2 p.Thr291= Pathogenic ★★ same type
CTU2 p.Ala176Val Uncertain significance ★★ ⚠ same type
CTU2 p.Ala400Thr Uncertain significance ★★ ⚠ same type
CTU2 p.Arg270Cys 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/ctu2-p-cys444ser (accessed [today's date]).

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