Is DPPA4 p.Lys59Glu (c.175A>G) pathogenic?

DPPA4 p.Lys59Glu (c.175A>G) is classified Uncertain significance in DPPA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: likely benign (0.0662); Very rare (popmax 0.00167%, amr).

How common is DPPA4 p.Lys59Glu (c.175A>G) in the general population?

DPPA4 p.Lys59Glu (c.175A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about DPPA4 p.Lys59Glu (c.175A>G)?

AlphaMissense predicts likely benign (score 0.0662) — an in-silico prediction, not a clinical call.

DPPA4 p.Lys59Glu

c.175A>G · VCV4662021

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0662 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0662	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -7.11	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 -0.13	GERP -3.4, phastCons 0.002
Regional constraint	o/e 1.05	unconstrained · MANE · 5,548 bp · p 0.66 · regional, not allelic
Overall
CADD	4.429	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,016 alleles

Overall 0.000137% 2/1,461,728 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,016
Remaining individualsnot grpmax-eligible	0.0016%	62,496

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: DPPA4
Protein: p.Lys59Glu
Coding: c.175A>G
MANE Select: NM_018189
Type: single nucleotide variant
Location: chr3:109333873 (GRCh38)
Gene constraint: LOEUF 0.901 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.05
Residue 59: the 'disordered' region

Full DPPA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DPPA4 p.Ala139Thr Uncertain significance ★ ⚠ same type
DPPA4 p.Ala201Pro Uncertain significance ★ ⚠ same type
DPPA4 p.Asn181His Uncertain significance ★ ⚠ same type
DPPA4 p.Asn34Asp Uncertain significance ★ ⚠ same type
DPPA4 p.Gln146Arg Uncertain significance ★ ⚠ same type
DPPA4 p.Gln223Lys Uncertain significance ★ ⚠ same type
DPPA4 p.Glu262Lys Uncertain significance ★ ⚠ same type
DPPA4 p.Gly174Arg 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/dppa4-p-lys59glu (accessed [today's date]).

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