Is DPP9 p.Glu422Lys (c.1264G>A) pathogenic?

DPP9 p.Glu422Lys (c.1264G>A) is classified Uncertain significance in DPP9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-13). AlphaMissense: likely benign (0.0693); Very rare (popmax 0.00354%, amr).

How common is DPP9 p.Glu422Lys (c.1264G>A) in the general population?

DPP9 p.Glu422Lys (c.1264G>A) is very rare (popmax 0.00354%, amr) (gnomAD).

What do computational predictors say about DPP9 p.Glu422Lys (c.1264G>A)?

AlphaMissense predicts likely benign (score 0.0693) — an in-silico prediction, not a clinical call.

DPP9 p.Glu422Lys

c.1264G>A · VCV4014653

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0693 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00354%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0693	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -5.86	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 2.1	GERP 1.7, phastCons 0.97
Regional constraint	o/e 0.88	unconstrained · MANE · 34 kb · p 0.00027 · regional, not allelic
Overall
CADD	16.59	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM E393K vs ClinVar E422K) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00354% Admixed American · 2/56,444 alleles

Filtering AF 0.000887% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000725%

Overall 0.00126% 20/1,585,720 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00354%	28,222
Remaining individualsnot grpmax-eligible	0.00163%	61,324
European (non-Finnish)	0.00146%	68,651

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: DPP9
Protein: p.Glu422Lys
Coding: c.1264G>A
MANE Select: NM_139159
Type: single nucleotide variant
Location: chr19:4695467 (GRCh38)
Gene constraint: LOEUF 0.647 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.96 · 14 PDB
Residue 422: a UniProt-annotated variant site (in hatis; likely pathogenic)

Full DPP9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DPP9 p.Asp310Asn Uncertain significance ★★ ⚠ same type
DPP9 p.Lys509Arg Uncertain significance ★★ ⚠ same type
DPP9 p.Thr301Met Uncertain significance ★★ ⚠ same type
DPP9 p.Ala184Gly Benign/Likely benign ★★ same type
DPP9 p.Glu566Lys Benign/Likely benign ★★ same type
DPP9 p.His83= Benign/Likely benign ★★ same type
DPP9 p.Pro322= Benign ★★ same type
DPP9 p.Ser236Asn Likely benign ★★ 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/dpp9-p-glu422lys (accessed [today's date]).

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