Is AGK p.Ile348fs (c.1039_1042dup) pathogenic?

AGK p.Ile348fs (c.10391042dup) is classified Pathogenic in AGK (ClinVar, Single submitter, 1 submitter; last evaluated 2018-12-23). Very rare (popmax 0.000849%, nfe); Associated with Sengers syndrome.

What condition is associated with AGK p.Ile348fs (c.1039_1042dup)?

AGK p.Ile348fs (c.1039_1042dup) is associated with Sengers syndrome (ClinVar).

How common is AGK p.Ile348fs (c.1039_1042dup) in the general population?

AGK p.Ile348fs (c.1039_1042dup) is very rare (popmax 0.000849%, nfe) (gnomAD).

AGK p.Ile348fs

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.1039_1042dup · rs778049466 · VCV1033892

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000849%, nfe)

Conditions

Sengers syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.2	GERP 5.6, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000849% European (non-Finnish) · 10/1,178,170 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.00062% 10/1,611,772 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.Ile348fs
Coding: c.1039_1042dup
MANE Select: NM_018238
dbSNP: rs778049466
Type: Duplication
Location: chr7:141649323 (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 348: a UniProt-annotated variant site (in mtdps10)

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

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

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

AGK p.Ile348Val Uncertain significance ★★ ⚠ same residue
AGK p.Ser382fs Pathogenic/Likely pathogenic ★★ same condition
AGK c.424-3dup Benign/Likely benign ★★ same condition
AGK c.1046_1046+1dup Pathogenic ★ same condition
AGK p.Ile120fs Pathogenic ★ same condition
AGK p.Ile346fs Pathogenic ★ same condition
AGK p.Tyr390fs Pathogenic ★ same condition
AGK c.101+4_101+7dup Likely benign ★ 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-ile348fs (accessed [today's date]).

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