Is AGPS p.Lys227Arg (c.680A>G) pathogenic?

AGPS p.Lys227Arg (c.680A>G) is classified Uncertain significance in AGPS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-29). AlphaMissense: likely benign (0.0799); Very rare (popmax 0.0033%, sas).

How common is AGPS p.Lys227Arg (c.680A>G) in the general population?

AGPS p.Lys227Arg (c.680A>G) is very rare (popmax 0.0033%, sas) (gnomAD).

What do computational predictors say about AGPS p.Lys227Arg (c.680A>G)?

AlphaMissense predicts likely benign (score 0.0799) — an in-silico prediction, not a clinical call.

AGPS p.Lys227Arg

c.680A>G · rs757432689 · VCV2917746

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0799 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0799	likely benign
REVEL	0.465	indeterminate
SaProt	LLR -9.71	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 4.7	GERP 0.98, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 145 kb · p 9.9e-28 · regional, not allelic
Overall
CADD	20.1	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 0.0033% South Asian · 3/91,006 alleles

Filtering AF 0.000876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000496% 8/1,612,862 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0033%	30,335
Finnishnot grpmax-eligible	0.00313%	31,968
Admixed American	0.00167%	59,984
European (non-Finnish)	0.00017%	589,657

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.Lys227Arg
Coding: c.680A>G
MANE Select: NM_003659
dbSNP: rs757432689
Type: single nucleotide variant
Location: chr2:177441007 (GRCh38)
Gene constraint: LOEUF 0.408 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.27
Residue 227: the fad-binding pcmh-type domain

Full AGPS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AGPS p.Lys227= Likely benign ★ same residue
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

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-lys227arg (accessed [today's date]).

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