Is AGK p.Thr64Ala (c.190A>G) pathogenic?

AGK p.Thr64Ala (c.190A>G) is classified Uncertain significance in AGK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-20). AlphaMissense: likely benign (0.2438); Very rare (popmax 0.00381%, nfe); Associated with Sengers syndrome.

What condition is associated with AGK p.Thr64Ala (c.190A>G)?

AGK p.Thr64Ala (c.190A>G) is associated with Sengers syndrome, cataract 38 (ClinVar).

How common is AGK p.Thr64Ala (c.190A>G) in the general population?

AGK p.Thr64Ala (c.190A>G) is very rare (popmax 0.00381%, nfe) (gnomAD).

What do computational predictors say about AGK p.Thr64Ala (c.190A>G)?

AlphaMissense predicts likely benign (score 0.2438) — an in-silico prediction, not a clinical call.

AGK p.Thr64Ala

Q: How is Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.190A>G · rs749193904 · VCV1903054

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2438 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00381%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Sengers syndrome

Computational evidence

Protein change
AlphaMissense	0.2438	likely benign
REVEL	0.311	indeterminate
SaProt	LLR -10.57	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 4.4, phastCons 1
Overall
CADD	26.2	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 0.00381% European (non-Finnish) · 45/1,179,978 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00308% 45/1,461,782 alleles · very rare

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.Thr64Ala
Coding: c.190A>G
MANE Select: NM_018238
dbSNP: rs749193904
Type: single nucleotide variant
Location: chr7:141596610 (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 64: the dagkc domain

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

Disease context

Sengers syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cataract 38

For Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

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
AGK p.Arg281Ter 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-thr64ala (accessed [today's date]).

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