Is DPP3 p.Arg76His (c.227G>A) pathogenic?

DPP3 p.Arg76His (c.227G>A) is classified Benign in DPP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-07-13). AlphaMissense: likely benign (0.0854); Common (popmax 7.29%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about DPP3 p.Arg76His (c.227G>A)?

AlphaMissense predicts likely benign (score 0.0854) — an in-silico prediction, not a clinical call.

DPP3 p.Arg76His

Q: How common is DPP3 p.Arg76His (c.227G>A) in the general population?

DPP3 p.Arg76His (c.227G>A) is common (popmax 7.29%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.227G>A · rs11826683 · VCV786198

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0854 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.29%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0854	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -8.33	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 1.4	GERP -3.3, phastCons 0.98
Regional constraint	o/e 0.86	unconstrained · MANE · 27 kb · p 1e-05 · regional, not allelic
Overall
CADD	21.2	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 7.29% African / African-American · 5,469/75,034 alleles

Filtering AF 7.13% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.06%

Overall 0.389% 6,255/1,608,834 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.29%	14
Admixed American	0.543%	184
Remaining individualsnot grpmax-eligible	0.477%	210
Middle Eastern	0.247%	404
South Asian	0.0242%	4,140
European (non-Finnish)	0.0106%	9,440

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.Arg76His
Coding: c.227G>A
MANE Select: NM_130443
dbSNP: rs11826683
Type: single nucleotide variant
Location: chr11:66482427 (GRCh38)
Gene constraint: LOEUF 0.827 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.56 · 10 PDB
Residue 76: an α-helix; a UniProt-annotated variant site (in)

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

Similar variants

DPP3 p.Arg76Cys Uncertain significance ★ ⚠ same residue
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-arg76his (accessed [today's date]).

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