Is AGK p.Pro300Leu (c.899C>T) pathogenic?

AGK p.Pro300Leu (c.899C>T) is classified Uncertain significance in AGK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-21). AlphaMissense: likely benign (0.0829); Very rare (popmax 0.00455%, eas); Associated with Inborn genetic diseases.

What condition is associated with AGK p.Pro300Leu (c.899C>T)?

AGK p.Pro300Leu (c.899C>T) is associated with Inborn genetic diseases, Sengers syndrome, cataract 38 (ClinVar).

How common is AGK p.Pro300Leu (c.899C>T) in the general population?

AGK p.Pro300Leu (c.899C>T) is very rare (popmax 0.00455%, eas) (gnomAD).

What do computational predictors say about AGK p.Pro300Leu (c.899C>T)?

AlphaMissense predicts likely benign (score 0.0829) — an in-silico prediction, not a clinical call.

AGK p.Pro300Leu

c.899C>T · rs143558063 · VCV2427756

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0829 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00455%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0829	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -8.17	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 2.7	GERP 4.1, phastCons 0.82
Overall
CADD	22.7	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 0.00455% East Asian · 2/43,928 alleles

Filtering AF 0.00311% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00348% 55/1,581,708 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00455%	21,964
European (non-Finnish)	0.00404%	24,742
African / African-American	0.00402%	24,896
South Asian	0.00232%	43,033
Admixed American	0.00181%	55,142

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: AGK
Protein: p.Pro300Leu
Coding: c.899C>T
MANE Select: NM_018238
dbSNP: rs143558063
Type: single nucleotide variant
Location: chr7:141641832 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.93 · 2 PDB
Residue 300: a UniProt-annotated variant site (in mtdps10)

Full AGK 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: Sengers syndrome cataract 38

Similar variants

AGK p.Pro300= Likely benign ★ same residue
AGK c.1047-2A>T Pathogenic/Likely pathogenic ★★ same condition
AGK c.222-2A>C Likely pathogenic ★★ same condition
AGK c.297+2T>C Pathogenic ★★ same condition
AGK c.424-3C>G Pathogenic/Likely pathogenic ★★ same condition
AGK c.518+1G>A Pathogenic ★★ same condition
AGK p.Arg137Ter Pathogenic ★★ same condition
AGK p.Arg138Ter Pathogenic ★★ 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/agk-p-pro300leu (accessed [today's date]).

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