Is AGPS p.Ala409Ser (c.1225G>T) pathogenic?

AGPS p.Ala409Ser (c.1225G>T) is classified Uncertain significance in AGPS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-30). AlphaMissense: likely benign (0.1321); Very rare (popmax 0.00231%, eas).

How common is AGPS p.Ala409Ser (c.1225G>T) in the general population?

AGPS p.Ala409Ser (c.1225G>T) is very rare (popmax 0.00231%, eas) (gnomAD).

What do computational predictors say about AGPS p.Ala409Ser (c.1225G>T)?

AlphaMissense predicts likely benign (score 0.1321) — an in-silico prediction, not a clinical call.

AGPS p.Ala409Ser

c.1225G>T · VCV4711112

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1321 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00231%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1321	likely benign
REVEL	0.604	indeterminate
SaProt	LLR -7.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 145 kb · p 9.9e-28 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00231% East Asian · 1/43,304 alleles

Overall 0.00019% 3/1,576,896 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00331%	30,219
East Asiangrpmax	0.00231%	43,304

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.Ala409Ser
Coding: c.1225G>T
MANE Select: NM_003659
Type: single nucleotide variant
Location: chr2:177482178 (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

Similar variants

AGPS p.Arg182Ter Pathogenic/Likely pathogenic ★★ same type
AGPS p.Thr309Ile Likely pathogenic ★★ same type
AGPS c.1855+6C>A Uncertain significance ★★ same type
AGPS c.*118A>G Uncertain significance ★★ same type
AGPS p.Arg265Gln Uncertain significance ★★ ⚠ same type
AGPS p.Asn649Ser Uncertain significance ★★ ⚠ same type
AGPS p.Asp28Val Uncertain significance ★★ ⚠ same type
AGPS p.Asp590His Uncertain significance ★★ ⚠ same type

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-ala409ser (accessed [today's date]).

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