Is AGPS p.Ile194Met (c.582A>G) pathogenic?

AGPS p.Ile194Met (c.582A>G) is classified Uncertain significance in AGPS (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-08-26). AlphaMissense: likely benign (0.1484); Absent from gnomAD v4.1; Associated with rhizomelic chondrodysplasia punctata.

What condition is associated with AGPS p.Ile194Met (c.582A>G)?

AGPS p.Ile194Met (c.582A>G) is associated with rhizomelic chondrodysplasia punctata (ClinVar).

How common is AGPS p.Ile194Met (c.582A>G) in the general population?

AGPS p.Ile194Met (c.582A>G) is absent from gnomAD v4.1 (gnomAD).

How is Rhizomelic chondrodysplasia punctata inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about AGPS p.Ile194Met (c.582A>G)?

AlphaMissense predicts likely benign (score 0.1484) — an in-silico prediction, not a clinical call.

AGPS p.Ile194Met

c.582A>G · rs1686432818 · VCV991246

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1484 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

rhizomelic chondrodysplasia punctata

Computational evidence

Protein change
AlphaMissense	0.1484	likely benign
REVEL	0.674	pathogenic-leaning
SaProt	LLR -6.38	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP 2, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 145 kb · p 9.9e-28 · regional, not allelic
Overall
CADD	22.4	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.Ile194Met
Coding: c.582A>G
MANE Select: NM_003659
dbSNP: rs1686432818
Type: single nucleotide variant
Location: chr2:177436999 (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

rhizomelic chondrodysplasia punctata — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Rhizomelic chondrodysplasia punctata (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

AGPS p.Thr309Ile Likely pathogenic ★★ same condition
AGPS c.261-5A>C Benign ★★ same condition
AGPS p.Ala69= Benign ★★ same condition
AGPS p.His362= Likely benign ★★ same condition
AGPS p.Pro415= Benign/Likely benign ★★ same condition
AGPS p.Pro49= Benign/Likely benign ★★ same condition
AGPS p.Ile194fs Likely pathogenic ★ same residue
AGPS p.Ala5Val 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-ile194met (accessed [today's date]).

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