Is AGK p.His248Pro (c.743A>C) pathogenic?

AGK p.His248Pro (c.743A>C) is classified Uncertain significance in AGK (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). AlphaMissense: ambiguous (0.4824); Rare (popmax 0.22%, afr); Associated with Inborn genetic diseases.

What condition is associated with AGK p.His248Pro (c.743A>C)?

AGK p.His248Pro (c.743A>C) is associated with Inborn genetic diseases, Sengers syndrome, cataract 38 (ClinVar).

How common is AGK p.His248Pro (c.743A>C) in the general population?

AGK p.His248Pro (c.743A>C) is rare (popmax 0.22%, afr) (gnomAD).

What do computational predictors say about AGK p.His248Pro (c.743A>C)?

AlphaMissense predicts ambiguous (score 0.4824) — an in-silico prediction, not a clinical call.

AGK p.His248Pro

c.743A>C · rs150160397 · VCV359061

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4824 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.22%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4824	ambiguous
REVEL	0.243	benign-leaning
SaProt	LLR -9.30	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 5.9, phastCons 1
Overall
CADD	24.4	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 0.22% African / African-American · 165/74,976 alleles

Filtering AF 0.193% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.182%

Overall 0.0115% 185/1,613,466 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.22%	454
Admixed American	0.015%	6,652
Remaining individualsnot grpmax-eligible	0.0128%	7,810
South Asian	0.0011%	90,984
European (non-Finnish)	0.00017%	589,877

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.His248Pro
Coding: c.743A>C
MANE Select: NM_018238
dbSNP: rs150160397
Type: single nucleotide variant
Location: chr7:141641264 (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 248: a UniProt-annotated variant site (in mtdps10)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Sengers syndrome cataract 38

Similar variants

AGK p.His248Tyr 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-his248pro (accessed [today's date]).

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