Is ADPGK p.Pro224Ser (c.670C>T) pathogenic?

ADPGK p.Pro224Ser (c.670C>T) is classified Uncertain significance in ADPGK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-01). Ultra-rare (popmax 0.0235%, nfe).

How common is ADPGK p.Pro224Ser (c.670C>T) in the general population?

ADPGK p.Pro224Ser (c.670C>T) is ultra-rare (popmax 0.0235%, nfe) (gnomAD).

ADPGK p.Pro224Ser

c.670C>T · VCV3273470

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0235%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.743	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 31 kb · p 0.0001 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0235% European (non-Finnish) · 277/1,180,030 alleles

Filtering AF 0.0212% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0203%

Overall 0.0178% 288/1,614,162 alleles · ultra-rare exomes 273/1,461,892 · genomes 15/152,270 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0235%	4,260
Remaining individualsnot grpmax-eligible	0.0128%	7,814
Admixed American	0.00167%	60,018
Finnishnot grpmax-eligible	0.00156%	64,028
African / African-American	0.00133%	75,040

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: ADPGK
Protein: p.Pro224Ser
Coding: c.670C>T
MANE Select: NM_001365225
Type: single nucleotide variant
Location: chr15:72756421 (GRCh38)
Gene constraint: LOEUF 0.937 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.36
Residue 224: the adpk domain

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

Similar variants

ADPGK p.Ala146Val Uncertain significance ★ same type
ADPGK p.Ala2Val Uncertain significance ★ same type
ADPGK p.Ala318Thr Uncertain significance ★ same type
ADPGK p.Ala318Val Uncertain significance ★ same type
ADPGK p.Ala416Thr Uncertain significance ★ same type
ADPGK p.Ala429Val Uncertain significance ★ same type
ADPGK p.Ala58Val Uncertain significance ★ same type
ADPGK p.Ala59Val Uncertain significance ★ 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/adpgk-p-pro224ser (accessed [today's date]).

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