Is CAGE1 p.Ala704Thr (c.2110G>A) pathogenic?

CAGE1 p.Ala704Thr (c.2110G>A) is classified Uncertain significance in CAGE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely benign (0.0866); Ultra-rare (popmax 0.0556%, nfe).

How common is CAGE1 p.Ala704Thr (c.2110G>A) in the general population?

CAGE1 p.Ala704Thr (c.2110G>A) is ultra-rare (popmax 0.0556%, nfe) (gnomAD).

What do computational predictors say about CAGE1 p.Ala704Thr (c.2110G>A)?

AlphaMissense predicts likely benign (score 0.0866) — an in-silico prediction, not a clinical call.

CAGE1 p.Ala704Thr

c.2110G>A · VCV4218215

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0866 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0556%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0866	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -5.43	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 -0.15	GERP -3, phastCons 0.018
Regional constraint	o/e 0.91	unconstrained · MANE · 60 kb · p 0.0056 · regional, not allelic
Overall
CADD	11.56	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 A677T vs ClinVar A704T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0556% European (non-Finnish) · 655/1,177,666 alleles

Filtering AF 0.052% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0506%

Overall 0.0419% 675/1,611,062 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0556%	1,798
Remaining individualsnot grpmax-eligible	0.016%	6,241
African / African-American	0.00534%	18,744
Admixed American	0.005%	19,986
Finnishnot grpmax-eligible	0.00469%	21,317

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.Ala704Thr
Coding: c.2110G>A
MANE Select: NM_001170692
Type: single nucleotide variant
Location: chr6:7365551 (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.Ala716Ser Uncertain significance ★ ⚠ same type
CAGE1 p.Arg281Trp Uncertain significance ★ ⚠ same type
CAGE1 p.Arg475Gln 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-ala704thr (accessed [today's date]).

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