Is AGPS p.Ile418Leu (c.1252A>C) pathogenic?

AGPS p.Ile418Leu (c.1252A>C) is classified Uncertain significance in AGPS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). AlphaMissense: ambiguous (0.3973); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with AGPS p.Ile418Leu (c.1252A>C)?

AGPS p.Ile418Leu (c.1252A>C) is associated with Inborn genetic diseases (ClinVar).

How common is AGPS p.Ile418Leu (c.1252A>C) in the general population?

AGPS p.Ile418Leu (c.1252A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AGPS p.Ile418Leu (c.1252A>C)?

AlphaMissense predicts ambiguous (score 0.3973) — an in-silico prediction, not a clinical call.

AGPS p.Ile418Leu

c.1252A>C · VCV4572465

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3973 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3973	ambiguous
REVEL	0.262	benign-leaning
SaProt	LLR -7.16	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 145 kb · p 9.9e-28 · regional, not allelic
Overall
CADD	19.53	PHRED · no single calibrated threshold — expert panels disagree

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: AGPS
Protein: p.Ile418Leu
Coding: c.1252A>C
MANE Select: NM_003659
Type: single nucleotide variant
Location: chr2:177493166 (GRCh38)
Gene constraint: LOEUF 0.408 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.27

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AGPS p.Arg265Gln Uncertain significance ★★ ⚠ same condition
AGPS p.Asn649Ser Uncertain significance ★★ ⚠ same condition
AGPS p.Asp590His Uncertain significance ★★ ⚠ same condition
AGPS p.Gly9Ala Uncertain significance ★★ ⚠ same condition
AGPS p.Leu120Val Uncertain significance ★★ ⚠ same condition
AGPS p.Phe450Leu Uncertain significance ★★ ⚠ same condition
AGPS p.Pro415Leu Uncertain significance ★★ ⚠ same condition
AGPS p.Pro460Ser Uncertain significance ★★ ⚠ same condition

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/agps-p-ile418leu (accessed [today's date]).

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