Is AGK p.Ile149Thr (c.446T>C) pathogenic?

AGK p.Ile149Thr (c.446T>C) is classified Uncertain significance in AGK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-15). AlphaMissense: likely pathogenic (0.6386); Rare (popmax 0.187%, sas); Associated with cataract 38.

What condition is associated with AGK p.Ile149Thr (c.446T>C)?

AGK p.Ile149Thr (c.446T>C) is associated with cataract 38, Sengers syndrome (ClinVar).

How common is AGK p.Ile149Thr (c.446T>C) in the general population?

AGK p.Ile149Thr (c.446T>C) is rare (popmax 0.187%, sas) (gnomAD).

How is Early onset non-syndromic cataract inherited?

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

What do computational predictors say about AGK p.Ile149Thr (c.446T>C)?

AlphaMissense predicts likely pathogenic (score 0.6386) — an in-silico prediction, not a clinical call.

AGK p.Ile149Thr

c.446T>C · rs560437625 · VCV2200142

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6386 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.187%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 38

Computational evidence

Protein change
AlphaMissense	0.6386	likely pathogenic
REVEL	0.649	pathogenic-leaning
SaProt	LLR -13.14	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 6.6, phastCons 1
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.187% South Asian · 170/91,012 alleles

Filtering AF 0.164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.155%

Overall 0.0113% 183/1,613,698 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.187%	535
Remaining individualsnot grpmax-eligible	0.0096%	10,413
East Asian	0.00223%	44,876
European (non-Finnish)	0.000509%	196,612

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.Ile149Thr
Coding: c.446T>C
MANE Select: NM_018238
dbSNP: rs560437625
Type: single nucleotide variant
Location: chr7:141615493 (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 149: the dagkc domain; a UniProt-annotated variant site (in mtdps10)

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

Disease context

cataract 38 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Sengers syndrome

For Early onset non-syndromic cataract (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

AGK p.Ile149Val Uncertain significance ★★ ⚠ 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-ile149thr (accessed [today's date]).

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