Is CTAGE1 p.Pro686Leu (c.2057C>T) pathogenic?

CTAGE1 p.Pro686Leu (c.2057C>T) is classified Uncertain significance in CTAGE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-17). AlphaMissense: likely benign (0.0927); Very rare (popmax 0.005%, amr).

How common is CTAGE1 p.Pro686Leu (c.2057C>T) in the general population?

CTAGE1 p.Pro686Leu (c.2057C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about CTAGE1 p.Pro686Leu (c.2057C>T)?

AlphaMissense predicts likely benign (score 0.0927) — an in-silico prediction, not a clinical call.

CTAGE1 p.Pro686Leu

c.2057C>T · VCV4007811

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0927 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0927	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -8.17	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 0.67	GERP 0.9, phastCons 0.18
Regional constraint	o/e 1.13	unconstrained · MANE · 2,234 bp · p 0.00025 · regional, not allelic
Overall
CADD	6.822	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 0.005% Admixed American · 3/60,010 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.0031% 50/1,613,942 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,003
European (non-Finnish)	0.00364%	27,439
Remaining individualsnot grpmax-eligible	0.0032%	31,246
Finnishnot grpmax-eligible	0.00312%	32,017

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.Pro686Leu
Coding: c.2057C>T
MANE Select: NM_172241
Type: single nucleotide variant
Location: chr18:22415755 (GRCh38)
Structure: AlphaFold pLDDT 70.45

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

Similar variants

CTAGE1 p.Pro686Thr Benign ★★ ⚠ same residue
CTAGE1 p.Ala169= Benign ★★ same type
CTAGE1 p.Ile682Met 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
CTAGE1 p.Ala332Thr 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-pro686leu (accessed [today's date]).

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