Is AGPS p.Lys553fs (c.1658_1659del) pathogenic?

AGPS p.Lys553fs (c.16581659del) is classified Likely pathogenic in AGPS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-04-17). Very rare (popmax 0.00017%, nfe); Associated with rhizomelic chondrodysplasia punctata.

What condition is associated with AGPS p.Lys553fs (c.1658_1659del)?

AGPS p.Lys553fs (c.1658_1659del) is associated with rhizomelic chondrodysplasia punctata (ClinVar).

How common is AGPS p.Lys553fs (c.1658_1659del) in the general population?

AGPS p.Lys553fs (c.1658_1659del) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Rhizomelic chondrodysplasia punctata inherited?

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

AGPS p.Lys553fs

c.1658_1659del · rs2468138958 · VCV2504001

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

rhizomelic chondrodysplasia punctata

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 17 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.7	GERP 1.9, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,644 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,422 alleles · very rare

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: AGPS
Protein: p.Lys553fs
Coding: c.1658_1659del
MANE Select: NM_003659
dbSNP: rs2468138958
Type: Deletion
Location: chr2:177513868 (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.Ala5Val Uncertain significance ★ ⚠ same condition
AGPS p.Arg50Trp Conflicting classifications of pathogenicity ★ ⚠ 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-lys553fs (accessed [today's date]).

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