Is AGK p.Leu294Pro (c.881T>C) pathogenic?

AGK p.Leu294Pro (c.881T>C) is classified Uncertain significance in AGK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-26). AlphaMissense: likely benign (0.0481); Very rare (popmax 0.00234%, sas); Associated with Sengers syndrome.

What condition is associated with AGK p.Leu294Pro (c.881T>C)?

AGK p.Leu294Pro (c.881T>C) is associated with Sengers syndrome, cataract 38 (ClinVar).

How common is AGK p.Leu294Pro (c.881T>C) in the general population?

AGK p.Leu294Pro (c.881T>C) is very rare (popmax 0.00234%, sas) (gnomAD).

What do computational predictors say about AGK p.Leu294Pro (c.881T>C)?

AlphaMissense predicts likely benign (score 0.0481) — an in-silico prediction, not a clinical call.

AGK p.Leu294Pro

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.881T>C · rs863223893 · VCV214071

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0481 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00234%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Sengers syndrome

Computational evidence

Protein change
AlphaMissense	0.0481	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -4.20	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 -1.9	GERP -7.5
Overall
CADD	5.302	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 0.00234% South Asian · 2/85,592 alleles

Filtering AF 0.000971% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000801%

Overall 0.00127% 20/1,573,974 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00234%	42,796
European (non-Finnish)	0.00155%	64,357

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.Leu294Pro
Coding: c.881T>C
MANE Select: NM_018238
dbSNP: rs863223893
Type: single nucleotide variant
Location: chr7:141641814 (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 294: 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

Also linked: cataract 38

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

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

AGK p.Leu294Ile Conflicting classifications of pathogenicity ★ ⚠ 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-leu294pro (accessed [today's date]).

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