Is AGPS p.Glu199Ter (c.595G>T) pathogenic?

AGPS p.Glu199Ter (c.595G>T) is classified Likely pathogenic in AGPS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-09). Absent from gnomAD v4.1; Associated with rhizomelic chondrodysplasia punctata type 3.

What condition is associated with AGPS p.Glu199Ter (c.595G>T)?

AGPS p.Glu199Ter (c.595G>T) is associated with rhizomelic chondrodysplasia punctata type 3 (ClinVar).

How common is AGPS p.Glu199Ter (c.595G>T) in the general population?

AGPS p.Glu199Ter (c.595G>T) 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.

AGPS p.Glu199Ter

c.595G>T · rs2468548402 · VCV2674927

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

rhizomelic chondrodysplasia punctata type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 5 of 20
Splicing
SpliceAI	Δ0.86	donor loss · deltas
Pangolin	Δ0.71	loss · gain 0.53 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Overall
CADD	50.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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.Glu199Ter
Coding: c.595G>T
MANE Select: NM_003659
dbSNP: rs2468548402
Type: single nucleotide variant
Location: chr2:177437012 (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 type 3 — 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.Glu199= Likely benign ★ same residue
AGPS p.Arg182Ter Pathogenic/Likely pathogenic ★★ same condition
AGPS p.Thr309Ile Likely pathogenic ★★ same condition
AGPS c.1855+6C>A Uncertain significance ★★ same condition
AGPS c.*118A>G Uncertain significance ★★ same condition
AGPS p.Asp28Val Uncertain significance ★★ ⚠ same condition
AGPS p.Pro415Leu Uncertain significance ★★ ⚠ same condition
AGPS p.Thr72Ala 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-glu199ter (accessed [today's date]).

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