Is CTAGE1 p.Pro689Ser (c.2065C>T) pathogenic?

CTAGE1 p.Pro689Ser (c.2065C>T) is classified Uncertain significance in CTAGE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely benign (0.1563); Very rare (popmax 0.00223%, eas).

How common is CTAGE1 p.Pro689Ser (c.2065C>T) in the general population?

CTAGE1 p.Pro689Ser (c.2065C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CTAGE1 p.Pro689Ser (c.2065C>T)?

AlphaMissense predicts likely benign (score 0.1563) — an in-silico prediction, not a clinical call.

CTAGE1 p.Pro689Ser

c.2065C>T · VCV4834956

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1563 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1563	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -8.11	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 3.4	GERP 0.79, phastCons 0.99
Regional constraint	o/e 1.13	unconstrained · MANE · 2,234 bp · p 0.00025 · regional, not allelic
Overall
CADD	9.56	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 0.00223% East Asian · 1/44,900 alleles

Overall 0.000186% 3/1,613,840 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,900
African / African-American	0.00134%	74,896
European (non-Finnish)	8.48e-05%	1,179,933

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: CTAGE1
Protein: p.Pro689Ser
Coding: c.2065C>T
MANE Select: NM_172241
Type: single nucleotide variant
Location: chr18:22415747 (GRCh38)
Structure: AlphaFold pLDDT 70.45

Full CTAGE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CTAGE1 p.Pro689Leu Uncertain significance ★ ⚠ same residue
CTAGE1 p.Ala169= Benign ★★ same type
CTAGE1 p.Ile682Met Benign ★★ same type
CTAGE1 p.Pro686Thr Benign ★★ ⚠ same type
CTAGE1 p.Val696Met Benign ★★ same type
CTAGE1 p.Ala181Val Uncertain significance ★ ⚠ same type
CTAGE1 p.Ala19Thr Uncertain significance ★ ⚠ same type
CTAGE1 p.Ala282Asp 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/ctage1-p-pro689ser (accessed [today's date]).

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