Is AGPS p.Val523= (c.1569A>G) pathogenic?

AGPS p.Val523= (c.1569A>G) is classified Conflicting classifications of pathogenicity in AGPS (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-25). Very rare (popmax 0.00439%, sas); Associated with rhizomelic chondrodysplasia punctata type 3.

What condition is associated with AGPS p.Val523= (c.1569A>G)?

AGPS p.Val523= (c.1569A>G) is associated with rhizomelic chondrodysplasia punctata type 3 (ClinVar).

How common is AGPS p.Val523= (c.1569A>G) in the general population?

AGPS p.Val523= (c.1569A>G) is very rare (popmax 0.00439%, sas) (gnomAD).

How is Rhizomelic chondrodysplasia punctata inherited?

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

AGPS p.Val523=

c.1569A>G · rs150977180 · VCV747115

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Conditions

rhizomelic chondrodysplasia punctata type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -2.4, phastCons 0.11
Overall
CADD	5.694	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,060 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00176%

Overall 0.00242% 39/1,613,044 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,765
Remaining individualsnot grpmax-eligible	0.0032%	31,224
European (non-Finnish)	0.0028%	35,733

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.Val523=
Coding: c.1569A>G
MANE Select: NM_003659
dbSNP: rs150977180
Type: single nucleotide variant
Location: chr2:177507993 (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.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
AGPS c.1233+14T>A Benign/Likely benign ★★ 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-val523 (accessed [today's date]).

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