Is CAGE1 p.Ser723Arg (c.2167A>C) pathogenic?

CAGE1 p.Ser723Arg (c.2167A>C) is classified Uncertain significance in CAGE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-05). AlphaMissense: likely benign (0.2322); Ultra-rare (popmax 0.0426%, afr).

How common is CAGE1 p.Ser723Arg (c.2167A>C) in the general population?

CAGE1 p.Ser723Arg (c.2167A>C) is ultra-rare (popmax 0.0426%, afr) (gnomAD).

What do computational predictors say about CAGE1 p.Ser723Arg (c.2167A>C)?

AlphaMissense predicts likely benign (score 0.2322) — an in-silico prediction, not a clinical call.

CAGE1 p.Ser723Arg

c.2167A>C · VCV3262939

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2322 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0426%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2322	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -6.91	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 0.43	GERP -1.1, phastCons 0.18
Regional constraint	o/e 0.91	unconstrained · MANE · 60 kb · p 0.0056 · regional, not allelic
Overall
CADD	19.15	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 S696R vs ClinVar S723R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0426% African / African-American · 32/75,050 alleles

Filtering AF 0.031% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0271%

Overall 0.00242% 39/1,613,530 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0426%	2,345
Remaining individualsnot grpmax-eligible	0.00961%	10,409
Admixed American	0.00167%	60,018

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.Ser723Arg
Coding: c.2167A>C
MANE Select: NM_001170692
Type: single nucleotide variant
Location: chr6:7365494 (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-ser723arg (accessed [today's date]).

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