Is DPP3 p.Ser408Leu (c.1223C>T) pathogenic?

DPP3 p.Ser408Leu (c.1223C>T) is classified Uncertain significance in DPP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-21). AlphaMissense: ambiguous (0.5415); Ultra-rare (popmax 0.0132%, sas).

How common is DPP3 p.Ser408Leu (c.1223C>T) in the general population?

DPP3 p.Ser408Leu (c.1223C>T) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

What do computational predictors say about DPP3 p.Ser408Leu (c.1223C>T)?

AlphaMissense predicts ambiguous (score 0.5415) — an in-silico prediction, not a clinical call.

DPP3 p.Ser408Leu

c.1223C>T · VCV3842265

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5415 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Computational evidence

Protein change
AlphaMissense	0.5415	ambiguous
REVEL	0.516	indeterminate
SaProt	LLR -13.52	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 27 kb · p 1e-05 · regional, not allelic
Overall
CADD	29.6	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 0.0132% South Asian · 12/91,070 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.00211% 34/1,614,026 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,589
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)	0.00153%	65,559
African / African-American	0.00133%	74,946

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: DPP3
Protein: p.Ser408Leu
Coding: c.1223C>T
MANE Select: NM_130443
Type: single nucleotide variant
Location: chr11:66493106 (GRCh38)
Gene constraint: LOEUF 0.827 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.56 · 10 PDB
Residue 408: a β-strand

Full DPP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DPP3 p.Arg76His Benign ★★ ⚠ same type
DPP3 p.Leu163Met Benign ★★ ⚠ same type
DPP3 p.Lys423= Benign ★★ same type
DPP3 p.Phe331= Benign ★★ same type
DPP3 p.Phe443= Benign ★★ same type
DPP3 p.Thr401= Benign ★★ same type
DPP3 c.573+1G>A Uncertain significance ★ same type
DPP3 p.Ala22Gly 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/dpp3-p-ser408leu (accessed [today's date]).

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