Is AGK p.Leu154Pro (c.461T>C) pathogenic?

AGK p.Leu154Pro (c.461T>C) is classified Uncertain significance in AGK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-05). AlphaMissense: likely pathogenic (0.9709); Very rare (popmax 0.00314%, nfe).

How common is AGK p.Leu154Pro (c.461T>C) in the general population?

AGK p.Leu154Pro (c.461T>C) is very rare (popmax 0.00314%, nfe) (gnomAD).

What do computational predictors say about AGK p.Leu154Pro (c.461T>C)?

AlphaMissense predicts likely pathogenic (score 0.9709) — an in-silico prediction, not a clinical call.

AGK p.Leu154Pro

c.461T>C · VCV4541340

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9709 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9709	likely pathogenic · top 4% in AGK
REVEL	0.498	indeterminate
SaProt	LLR -14.24	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 6.6, phastCons 1
Overall
CADD	28.9	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 0.00314% European (non-Finnish) · 37/1,179,884 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00229% 37/1,613,886 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.Leu154Pro
Coding: c.461T>C
MANE Select: NM_018238
Type: single nucleotide variant
Location: chr7:141615508 (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 154: the dagkc domain; a UniProt-annotated variant site (in mtdps10)

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

Similar variants

AGK p.Leu154= Likely benign ★ same residue
AGK c.1047-2A>T Pathogenic/Likely pathogenic ★★ same type
AGK c.222-2A>C Likely pathogenic ★★ same type
AGK c.297+2T>C Pathogenic ★★ same type
AGK c.424-3C>G Pathogenic/Likely pathogenic ★★ same type
AGK c.518+1G>A Pathogenic ★★ same type
AGK p.Arg137Ter Pathogenic ★★ same type
AGK p.Arg138Ter Pathogenic ★★ same type

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-leu154pro (accessed [today's date]).

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