Is CTAGE9 p.Leu440Arg (c.1319T>G) pathogenic?

CTAGE9 p.Leu440Arg (c.1319T>G) is classified Uncertain significance in CTAGE9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely benign (0.1829); Ultra-rare (popmax 0.0174%, afr).

How common is CTAGE9 p.Leu440Arg (c.1319T>G) in the general population?

CTAGE9 p.Leu440Arg (c.1319T>G) is ultra-rare (popmax 0.0174%, afr) (gnomAD).

What do computational predictors say about CTAGE9 p.Leu440Arg (c.1319T>G)?

AlphaMissense predicts likely benign (score 0.1829) — an in-silico prediction, not a clinical call.

CTAGE9 p.Leu440Arg

c.1319T>G · VCV4235483

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1829 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1829	likely benign
REVEL	0.268	benign-leaning
SaProt	LLR -6.39	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 0.65, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 222 bp · p 0.0021 · regional, not allelic
Overall
CADD	18.81	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 0.0174% African / African-American · 13/74,844 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.000868% 14/1,613,628 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,757
Remaining individualsnot grpmax-eligible	0.0016%	62,468

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: CTAGE9
Protein: p.Leu440Arg
Coding: c.1319T>G
MANE Select: NM_001145659
Type: single nucleotide variant
Location: chr6:131709699 (GRCh38)
Gene constraint: LOEUF 1.713 · pLI 0.41 (gnomAD)
Structure: AlphaFold pLDDT 69.37

Full CTAGE9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CTAGE9 p.Ala120Thr Uncertain significance ★ ⚠ same type
CTAGE9 p.Ala120Val Uncertain significance ★ ⚠ same type
CTAGE9 p.Ala122Val Uncertain significance ★ ⚠ same type
CTAGE9 p.Ala168Val Uncertain significance ★ ⚠ same type
CTAGE9 p.Ala208Val Uncertain significance ★ ⚠ same type
CTAGE9 p.Ala280Val Uncertain significance ★ ⚠ same type
CTAGE9 p.Ala321Thr Uncertain significance ★ ⚠ same type
CTAGE9 p.Ala48Pro 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/ctage9-p-leu440arg (accessed [today's date]).

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