Is AGPS p.Pro533Thr (c.1597C>A) pathogenic?

AGPS p.Pro533Thr (c.1597C>A) is classified Uncertain significance in AGPS (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: ambiguous (0.4337); Very rare (popmax 8.49e-05%, nfe); Associated with rhizomelic chondrodysplasia punctata type 3.

What condition is associated with AGPS p.Pro533Thr (c.1597C>A)?

AGPS p.Pro533Thr (c.1597C>A) is associated with rhizomelic chondrodysplasia punctata type 3 (ClinVar).

How common is AGPS p.Pro533Thr (c.1597C>A) in the general population?

AGPS p.Pro533Thr (c.1597C>A) is very rare (popmax 8.49e-05%, nfe) (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.Pro533Thr (c.1597C>A)?

AlphaMissense predicts ambiguous (score 0.4337) — an in-silico prediction, not a clinical call.

AGPS p.Pro533Thr

c.1597C>A · rs886055167 · VCV332521

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4337 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

rhizomelic chondrodysplasia punctata type 3

Computational evidence

Protein change
AlphaMissense	0.4337	ambiguous
REVEL	0.884	moderately pathogenic-leaning
SaProt	LLR -8.82	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 145 kb · p 9.9e-28 · regional, not allelic
Overall
CADD	26.5	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

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,177,836 alleles

Overall 0.000137% 2/1,459,216 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,422
European (non-Finnish)grpmax	8.49e-05%	1,177,835

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro533Thr
Coding: c.1597C>A
MANE Select: NM_003659
dbSNP: rs886055167
Type: single nucleotide variant
Location: chr2:177508021 (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.Pro533= 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-pro533thr (accessed [today's date]).

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