Is AGPS p.Asn649Ser (c.1946A>G) pathogenic?

AGPS p.Asn649Ser (c.1946A>G) is classified Uncertain significance in AGPS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-10). AlphaMissense: likely benign (0.0661); Ultra-rare (popmax 0.0184%, amr); Associated with Inborn genetic diseases.

What condition is associated with AGPS p.Asn649Ser (c.1946A>G)?

AGPS p.Asn649Ser (c.1946A>G) is associated with Inborn genetic diseases (ClinVar).

How common is AGPS p.Asn649Ser (c.1946A>G) in the general population?

AGPS p.Asn649Ser (c.1946A>G) is ultra-rare (popmax 0.0184%, amr) (gnomAD).

What do computational predictors say about AGPS p.Asn649Ser (c.1946A>G)?

AlphaMissense predicts likely benign (score 0.0661) — an in-silico prediction, not a clinical call.

AGPS p.Asn649Ser

c.1946A>G · rs754151191 · VCV2062716

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0661 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0184%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0661	likely benign
REVEL	0.268	benign-leaning
SaProt	LLR -7.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 1, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 145 kb · p 9.9e-28 · regional, not allelic
Overall
CADD	17.7	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 0.0184% Admixed American · 11/59,934 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00786%

Overall 0.00178% 26/1,460,826 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0184%	5,449
Remaining individualsnot grpmax-eligible	0.00801%	12,492
East Asian	0.00223%	44,856
South Asian	0.0011%	91,064
European (non-Finnish)	0.000678%	147,397

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.Asn649Ser
Coding: c.1946A>G
MANE Select: NM_003659
dbSNP: rs754151191
Type: single nucleotide variant
Location: chr2:177538164 (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.Arg265Gln 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
AGPS p.Pro460Ser 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-asn649ser (accessed [today's date]).

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