Is CAGE1 p.Leu728Pro (c.2183T>C) pathogenic?

CAGE1 p.Leu728Pro (c.2183T>C) is classified Uncertain significance in CAGE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-20). AlphaMissense: likely pathogenic (0.8984); Very rare (popmax 0.00893%, eas).

How common is CAGE1 p.Leu728Pro (c.2183T>C) in the general population?

CAGE1 p.Leu728Pro (c.2183T>C) is very rare (popmax 0.00893%, eas) (gnomAD).

What do computational predictors say about CAGE1 p.Leu728Pro (c.2183T>C)?

AlphaMissense predicts likely pathogenic (score 0.8984) — an in-silico prediction, not a clinical call.

CAGE1 p.Leu728Pro

c.2183T>C · rs776245516 · VCV2238970

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8984 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00893%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8984	likely pathogenic · top 1% in CAGE1
REVEL	0.46	indeterminate
SaProt	LLR -13.84	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 60 kb · p 0.0056 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 L701P vs ClinVar L728P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00893% East Asian · 4/44,798 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000411% 6/1,460,388 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00893%	11,200
Remaining individualsnot grpmax-eligible	0.0016%	62,430
European (non-Finnish)	8.48e-05%	1,179,330

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.Leu728Pro
Coding: c.2183T>C
MANE Select: NM_001170692
dbSNP: rs776245516
Type: single nucleotide variant
Location: chr6:7365478 (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

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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-leu728pro (accessed [today's date]).

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