Is AGPS p.Pro460Ser (c.1378C>T) pathogenic?

AGPS p.Pro460Ser (c.1378C>T) is classified Uncertain significance in AGPS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-10-31). AlphaMissense: ambiguous (0.343); Ultra-rare (popmax 0.0184%, amr); Associated with Inborn genetic diseases.

What condition is associated with AGPS p.Pro460Ser (c.1378C>T)?

AGPS p.Pro460Ser (c.1378C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AGPS p.Pro460Ser (c.1378C>T) in the general population?

AGPS p.Pro460Ser (c.1378C>T) is ultra-rare (popmax 0.0184%, amr) (gnomAD).

What do computational predictors say about AGPS p.Pro460Ser (c.1378C>T)?

AlphaMissense predicts ambiguous (score 0.343) — an in-silico prediction, not a clinical call.

AGPS p.Pro460Ser

c.1378C>T · rs761526892 · VCV2141120

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.343 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0184%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.343	ambiguous
REVEL	0.572	indeterminate
SaProt	LLR -8.63	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 145 kb · p 9.9e-28 · regional, not allelic
Overall
CADD	23.9	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 0.0184% Admixed American · 11/59,824 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00797%

Overall 0.00106% 17/1,607,748 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0184%	5,439
African / African-American	0.00268%	37,260
Remaining individualsnot grpmax-eligible	0.00161%	62,238
European (non-Finnish)	0.000255%	392,138

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.Pro460Ser
Coding: c.1378C>T
MANE Select: NM_003659
dbSNP: rs761526892
Type: single nucleotide variant
Location: chr2:177499633 (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

Similar variants

AGPS p.Pro460= Conflicting classifications of pathogenicity ★ same residue
AGPS p.Arg265Gln Uncertain significance ★★ ⚠ same condition
AGPS p.Asn649Ser Uncertain significance ★★ ⚠ same condition
AGPS p.Asp590His Uncertain significance ★★ ⚠ same condition
AGPS p.Gly9Ala Uncertain significance ★★ ⚠ same condition
AGPS p.Leu120Val Uncertain significance ★★ ⚠ same condition
AGPS p.Phe450Leu Uncertain significance ★★ ⚠ same condition
AGPS p.Pro415Leu 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-pro460ser (accessed [today's date]).

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