Is AGPS p.Leu469Pro (c.1406T>C) pathogenic?

AGPS p.Leu469Pro (c.1406T>C) is classified Pathogenic in AGPS (ClinVar, No assertion criteria, 1 submitter; last evaluated 2001-01-15). AlphaMissense: likely pathogenic (0.9978); Absent from gnomAD v4.1; Associated with rhizomelic chondrodysplasia punctata type 3.

What condition is associated with AGPS p.Leu469Pro (c.1406T>C)?

AGPS p.Leu469Pro (c.1406T>C) is associated with rhizomelic chondrodysplasia punctata type 3 (ClinVar).

How common is AGPS p.Leu469Pro (c.1406T>C) in the general population?

AGPS p.Leu469Pro (c.1406T>C) 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.Leu469Pro (c.1406T>C)?

AlphaMissense predicts likely pathogenic (score 0.9978) — an in-silico prediction, not a clinical call.

AGPS p.Leu469Pro

c.1406T>C · rs121434413 · VCV6647

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9978 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

rhizomelic chondrodysplasia punctata type 3

Computational evidence

Protein change
AlphaMissense	0.9978	likely pathogenic ✓ concordant with ClinVar · top 3% in AGPS
REVEL	0.868	moderately pathogenic-leaning
SaProt	LLR -14.48	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2.3, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 145 kb · p 9.9e-28 · regional, not allelic
Overall
CADD	28.0	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.Leu469Pro
Coding: c.1406T>C
MANE Select: NM_003659
dbSNP: rs121434413
Type: single nucleotide variant
Location: chr2:177499661 (GRCh38)
Gene constraint: LOEUF 0.408 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.27
Residue 469: a UniProt-annotated variant site (in rcdp3)

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.Leu469= 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-leu469pro (accessed [today's date]).

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