Is DPP6 p.Ala20Thr (c.58G>A) pathogenic?

DPP6 p.Ala20Thr (c.58G>A) is classified Conflicting classifications of pathogenicity in DPP6 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-02-16). AlphaMissense: likely benign (0.0796); Ultra-rare (popmax 0.0435%, amr); Associated with intellectual disability, autosomal dominant 33.

What condition is associated with DPP6 p.Ala20Thr (c.58G>A)?

DPP6 p.Ala20Thr (c.58G>A) is associated with intellectual disability, autosomal dominant 33, ventricular fibrillation, paroxysmal familial, 2 (ClinVar).

How common is DPP6 p.Ala20Thr (c.58G>A) in the general population?

DPP6 p.Ala20Thr (c.58G>A) is ultra-rare (popmax 0.0435%, amr) (gnomAD).

What do computational predictors say about DPP6 p.Ala20Thr (c.58G>A)?

AlphaMissense predicts likely benign (score 0.0796) — an in-silico prediction, not a clinical call.

DPP6 p.Ala20Thr

c.58G>A · rs2533731 · VCV1049455

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0796 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0435%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal dominant 33

Computational evidence

Protein change
AlphaMissense	0.0796	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -7.31	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 7.5	GERP 2.3, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 840 kb · p 1.6e-08 · regional, not allelic
Overall
CADD	22.6	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 0.0435% Admixed American · 22/50,546 alleles

Filtering AF 0.0294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0248%

Overall 0.0289% 444/1,534,558 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.305%	328
Admixed Americangrpmax	0.0435%	2,298
Remaining individualsnot grpmax-eligible	0.0303%	3,303
European (non-Finnish)	0.0271%	3,693
East Asian	0.00747%	13,378
South Asian	0.00477%	20,967
Finnishnot grpmax-eligible	0.00191%	52,410
African / African-American	0.00139%	72,108

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: DPP6
Protein: p.Ala20Thr
Coding: c.58G>A
MANE Select: NM_130797
dbSNP: rs2533731
Type: single nucleotide variant
Location: chr7:154052878 (GRCh38)
Gene constraint: LOEUF 0.751 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 87.41 · 8 PDB
Residue 20: the 'disordered' region

Full DPP6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability, autosomal dominant 33 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ventricular fibrillation, paroxysmal familial, 2

Similar variants

DPP6 p.Lys223Arg Uncertain significance ★★ ⚠ same condition
DPP6 p.Pro229Thr Uncertain significance ★★ ⚠ same condition
DPP6 p.Gln271= Benign ★★ same condition
DPP6 p.Lys241= Benign ★★ same condition
DPP6 p.Arg775Ter Likely pathogenic ★ same condition
DPP6 p.Tyr205Ter Likely pathogenic ★ same condition
DPP6 c.1667-4A>G Uncertain significance ★ same condition
DPP6 c.2304+2T>C Uncertain significance ★ same condition

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/dpp6-p-ala20thr (accessed [today's date]).

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