Is AGER p.Ile126Ser (c.377T>G) pathogenic?

AGER p.Ile126Ser (c.377T>G) is classified Uncertain significance in AGER (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-07). AlphaMissense: likely pathogenic (0.6847); Absent from gnomAD v4.1.

How common is AGER p.Ile126Ser (c.377T>G) in the general population?

AGER p.Ile126Ser (c.377T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AGER p.Ile126Ser (c.377T>G)?

AlphaMissense predicts likely pathogenic (score 0.6847) — an in-silico prediction, not a clinical call.

AGER p.Ile126Ser

c.377T>G · VCV3275790

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6847 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6847	likely pathogenic · top 8% in AGER
REVEL	0.741	pathogenic-leaning
SaProt	LLR -13.09	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 3,076 bp · p 0.25 · regional, not allelic
Overall
CADD	25.0	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AGER
Protein: p.Ile126Ser
Coding: c.377T>G
MANE Select: NM_001136
Type: single nucleotide variant
Location: chr6:32183367 (GRCh38)
Gene constraint: LOEUF 1.068 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.74 · 33 PDB
Residue 126: a β-strand; the ig-like c2-type 1 domain

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

Similar variants

AGER p.Ala19Gly Uncertain significance ★ ⚠ same type
AGER p.Ala355Thr Uncertain significance ★ ⚠ same type
AGER p.Ala375Ser Uncertain significance ★ ⚠ same type
AGER p.Ala41Val Uncertain significance ★ ⚠ same type
AGER p.Ala6Val Uncertain significance ★ ⚠ same type
AGER p.Ala76Val Uncertain significance ★ ⚠ same type
AGER p.Arg116Leu Uncertain significance ★ ⚠ same type
AGER p.Arg178Ser 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/ager-p-ile126ser (accessed [today's date]).

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