Is AGPS p.Pro415Leu (c.1244C>T) pathogenic?

AGPS p.Pro415Leu (c.1244C>T) is classified Uncertain significance in AGPS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-21). AlphaMissense: likely pathogenic (0.981); Ultra-rare (popmax 0.0167%, mid); Associated with Inborn genetic diseases.

What condition is associated with AGPS p.Pro415Leu (c.1244C>T)?

AGPS p.Pro415Leu (c.1244C>T) is associated with Inborn genetic diseases, rhizomelic chondrodysplasia punctata type 3 (ClinVar).

How common is AGPS p.Pro415Leu (c.1244C>T) in the general population?

AGPS p.Pro415Leu (c.1244C>T) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about AGPS p.Pro415Leu (c.1244C>T)?

AlphaMissense predicts likely pathogenic (score 0.981) — an in-silico prediction, not a clinical call.

AGPS p.Pro415Leu

c.1244C>T · rs144444120 · VCV892844

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.981 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.981	likely pathogenic
REVEL	0.816	moderately pathogenic-leaning
SaProt	LLR -13.89	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 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 145 kb · p 9.9e-28 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Middle Eastern · 1/6,006 alleles

Filtering AF 0.0047% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00431%

Overall 0.00515% 83/1,612,952 alleles · ultra-rare exomes 78/1,460,894 · genomes 5/152,058 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	6,006
European (non-Finnish)	0.00585%	17,094
South Asian	0.00549%	18,211
African / African-American	0.00534%	18,720
Admixed American	0.005%	20,004
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Pro415Leu
Coding: c.1244C>T
MANE Select: NM_003659
dbSNP: rs144444120
Type: single nucleotide variant
Location: chr2:177493158 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: rhizomelic chondrodysplasia punctata type 3

Similar variants

AGPS p.Pro415= Benign/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.Arg265Gln Uncertain significance ★★ ⚠ same condition
AGPS p.Asn649Ser Uncertain significance ★★ ⚠ same condition
AGPS p.Asp28Val 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-pro415leu (accessed [today's date]).

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