Is CTU2 p.Pro216Leu (c.647C>T) pathogenic?

CTU2 p.Pro216Leu (c.647C>T) is classified Uncertain significance in CTU2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-10). AlphaMissense: likely benign (0.0652); Very rare (popmax 0.00536%, afr).

How common is CTU2 p.Pro216Leu (c.647C>T) in the general population?

CTU2 p.Pro216Leu (c.647C>T) is very rare (popmax 0.00536%, afr) (gnomAD).

What do computational predictors say about CTU2 p.Pro216Leu (c.647C>T)?

AlphaMissense predicts likely benign (score 0.0652) — an in-silico prediction, not a clinical call.

CTU2 p.Pro216Leu

c.647C>T · rs146775425 · VCV3078890

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0652 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00536%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0652	likely benign
REVEL	0.007	strongly benign-leaning
SaProt	LLR -7.93	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 -1.6	GERP -4.2
Regional constraint	o/e 1.61	unconstrained · MANE · 8,717 bp · p 1.9e-57 · regional, not allelic
Overall
CADD	0.133	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 0.00536% African / African-American · 4/74,646 alleles

Filtering AF 0.00308% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00368% 59/1,603,292 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00536%	18,661
East Asian	0.00446%	22,399
European (non-Finnish)	0.004%	25,011
Admixed American	0.00338%	29,551
Remaining individualsnot grpmax-eligible	0.00323%	30,990
South Asian	0.00222%	45,019

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.Pro216Leu
Coding: c.647C>T
MANE Select: NM_001012759
dbSNP: rs146775425
Type: single nucleotide variant
Location: chr16:88712815 (GRCh38)
Gene constraint: LOEUF 1.535 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.27
Residue 216: the 'disordered' region

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

Similar variants

CTU2 p.Pro216Gln Uncertain significance ★ ⚠ same residue
CTU2 p.Pro216= 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

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-pro216leu (accessed [today's date]).

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