Is CTU2 p.Pro216Gln (c.647C>A) pathogenic?

CTU2 p.Pro216Gln (c.647C>A) is classified Uncertain significance in CTU2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-09). AlphaMissense: likely benign (0.0817); Very rare (popmax 0.00938%, afr).

How common is CTU2 p.Pro216Gln (c.647C>A) in the general population?

CTU2 p.Pro216Gln (c.647C>A) is very rare (popmax 0.00938%, afr) (gnomAD).

What do computational predictors say about CTU2 p.Pro216Gln (c.647C>A)?

AlphaMissense predicts likely benign (score 0.0817) — an in-silico prediction, not a clinical call.

CTU2 p.Pro216Gln

c.647C>A · VCV3498547

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0817 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00938%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0817	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -7.60	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	0.069	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 0.00938% African / African-American · 7/74,646 alleles

Filtering AF 0.00439% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.000437% 7/1,603,294 alleles · very rare

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.Pro216Gln
Coding: c.647C>A
MANE Select: NM_001012759
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.Pro216Leu 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-pro216gln (accessed [today's date]).

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