Is DPP9 p.Phe740Leu (c.2220C>A) pathogenic?

DPP9 p.Phe740Leu (c.2220C>A) is classified Uncertain significance in DPP9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-05). AlphaMissense: likely pathogenic (0.8589); Ultra-rare (popmax 0.0164%, mid).

How common is DPP9 p.Phe740Leu (c.2220C>A) in the general population?

DPP9 p.Phe740Leu (c.2220C>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about DPP9 p.Phe740Leu (c.2220C>A)?

AlphaMissense predicts likely pathogenic (score 0.8589) — an in-silico prediction, not a clinical call.

DPP9 p.Phe740Leu

c.2220C>A · rs775362476 · VCV2609804

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8589 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8589	likely pathogenic
REVEL	0.099	moderately benign-leaning
SaProt	LLR -8.61	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -3.6
Regional constraint	o/e 0.75	unconstrained · MANE · 8,223 bp · p 2e-05 · regional, not allelic
Overall
CADD	1.082	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F711L vs ClinVar F740L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000496% 8/1,613,412 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Admixed American	0.00167%	60,010
African / African-American	0.00133%	74,912
European (non-Finnish)	0.000424%	235,973

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.Phe740Leu
Coding: c.2220C>A
MANE Select: NM_139159
dbSNP: rs775362476
Type: single nucleotide variant
Location: chr19:4683588 (GRCh38)
Gene constraint: LOEUF 0.647 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.96 · 14 PDB
Residue 740: a UniProt-annotated variant site (in hatis; likely pathogenic); an α-helix

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-phe740leu (accessed [today's date]).

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