Is DPP3 p.Val538Met (c.1612G>A) pathogenic?

DPP3 p.Val538Met (c.1612G>A) is classified Uncertain significance in DPP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-07). AlphaMissense: ambiguous (0.404); Very rare (popmax 0.004%, afr).

How common is DPP3 p.Val538Met (c.1612G>A) in the general population?

DPP3 p.Val538Met (c.1612G>A) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about DPP3 p.Val538Met (c.1612G>A)?

AlphaMissense predicts ambiguous (score 0.404) — an in-silico prediction, not a clinical call.

DPP3 p.Val538Met

c.1612G>A · rs1346296209 · VCV2535106

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.404 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Computational evidence

Protein change
AlphaMissense	0.404	ambiguous
REVEL	0.348	indeterminate
SaProt	LLR -10.73	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 27 kb · p 1e-05 · regional, not allelic
Overall
CADD	29.1	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 0.004% African / African-American · 3/74,942 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000496% 8/1,614,008 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,981
East Asian	0.00223%	44,884
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000254%	393,340

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.Val538Met
Coding: c.1612G>A
MANE Select: NM_130443
dbSNP: rs1346296209
Type: single nucleotide variant
Location: chr11:66495664 (GRCh38)
Gene constraint: LOEUF 0.827 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.56 · 10 PDB
Residue 538: an α-helix

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-val538met (accessed [today's date]).

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