Is CAGE1 p.Pro821Leu (c.2462C>T) pathogenic?

CAGE1 p.Pro821Leu (c.2462C>T) is classified Uncertain significance in CAGE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). AlphaMissense: likely benign (0.1361); Ultra-rare (popmax 0.0367%, amr).

How common is CAGE1 p.Pro821Leu (c.2462C>T) in the general population?

CAGE1 p.Pro821Leu (c.2462C>T) is ultra-rare (popmax 0.0367%, amr) (gnomAD).

What do computational predictors say about CAGE1 p.Pro821Leu (c.2462C>T)?

AlphaMissense predicts likely benign (score 0.1361) — an in-silico prediction, not a clinical call.

CAGE1 p.Pro821Leu

c.2462C>T · rs142647100 · VCV2411731

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1361 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0367%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1361	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -5.60	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 1.9	GERP -0.47, phastCons 0.98
Regional constraint	o/e 0.91	unconstrained · MANE · 60 kb · p 0.0056 · regional, not allelic
Overall
CADD	16.82	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P759L vs ClinVar P821L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0367% Admixed American · 20/54,524 alleles

Filtering AF 0.0243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0203%

Overall 0.00439% 64/1,458,374 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0367%	2,726
South Asian	0.0314%	3,185
African / African-American	0.00693%	14,436
European (non-Finnish)	0.00124%	80,868

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: CAGE1
Protein: p.Pro821Leu
Coding: c.2462C>T
MANE Select: NM_001170692
dbSNP: rs142647100
Type: single nucleotide variant
Location: chr6:7329865 (GRCh38)
Gene constraint: LOEUF 0.792 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.17

Full CAGE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAGE1 p.Ala132Thr Uncertain significance ★ ⚠ same type
CAGE1 p.Ala469Val Uncertain significance ★ ⚠ same type
CAGE1 p.Ala566Thr Uncertain significance ★ ⚠ same type
CAGE1 p.Ala605Val Uncertain significance ★ ⚠ same type
CAGE1 p.Ala622Thr Uncertain significance ★ ⚠ same type
CAGE1 p.Ala704Thr Uncertain significance ★ ⚠ same type
CAGE1 p.Ala716Ser Uncertain significance ★ ⚠ same type
CAGE1 p.Arg281Trp 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/cage1-p-pro821leu (accessed [today's date]).

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