Is CTU2 p.Pro481Leu (c.1442C>T) pathogenic?

CTU2 p.Pro481Leu (c.1442C>T) is classified Uncertain significance in CTU2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-02). AlphaMissense: likely benign (0.1607); Ultra-rare (popmax 0.017%, mid).

How common is CTU2 p.Pro481Leu (c.1442C>T) in the general population?

CTU2 p.Pro481Leu (c.1442C>T) is ultra-rare (popmax 0.017%, mid) (gnomAD).

What do computational predictors say about CTU2 p.Pro481Leu (c.1442C>T)?

AlphaMissense predicts likely benign (score 0.1607) — an in-silico prediction, not a clinical call.

CTU2 p.Pro481Leu

c.1442C>T · VCV3361930

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1607 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.017%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1607	likely benign
REVEL	0.242	benign-leaning
SaProt	LLR -8.48	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 3.2	GERP 1.2, phastCons 0.97
Regional constraint	o/e 1.61	unconstrained · MANE · 8,717 bp · p 1.9e-57 · regional, not allelic
Overall
CADD	20.7	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 0.017% Middle Eastern · 1/5,888 alleles

Filtering AF 0.0071% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00653%

Overall 0.0082% 129/1,573,746 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.017%	5,888
Admixed American	0.0121%	8,232
African / African-American	0.0121%	8,272
East Asian	0.00901%	11,098
European (non-Finnish)	0.00846%	11,821
South Asian	0.00819%	12,210
Finnishnot grpmax-eligible	0.00341%	29,293
Remaining individualsnot grpmax-eligible	0.00165%	60,760

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.Pro481Leu
Coding: c.1442C>T
MANE Select: NM_001012759
Type: single nucleotide variant
Location: chr16:88715070 (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.Pro481= Likely 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-pro481leu (accessed [today's date]).

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