Is DLK2 p.Pro23Arg (c.68C>G) pathogenic?

DLK2 p.Pro23Arg (c.68C>G) is classified Uncertain significance in DLK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-12). AlphaMissense: likely benign (0.0944); Very rare (popmax 0.00193%, amr).

How common is DLK2 p.Pro23Arg (c.68C>G) in the general population?

DLK2 p.Pro23Arg (c.68C>G) is very rare (popmax 0.00193%, amr) (gnomAD).

What do computational predictors say about DLK2 p.Pro23Arg (c.68C>G)?

AlphaMissense predicts likely benign (score 0.0944) — an in-silico prediction, not a clinical call.

DLK2 p.Pro23Arg

c.68C>G · VCV4012129

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0944 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00193%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0944	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -6.43	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 6.3	GERP -0.6, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 4,283 bp · p 1.3e-09 · regional, not allelic
Overall
CADD	22.0	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 0.00193% Admixed American · 1/51,850 alleles

Overall 0.000129% 2/1,553,024 alleles · very rare exomes 1/1,403,416 · genomes 1/149,608 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00193%	51,850
European (non-Finnish)	8.66e-05%	1,154,862

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: DLK2
Protein: p.Pro23Arg
Coding: c.68C>G
MANE Select: NM_023932
Type: single nucleotide variant
Location: chr6:43454758 (GRCh38)
Gene constraint: LOEUF 0.526 · pLI 0.96 (gnomAD)
Structure: AlphaFold pLDDT 74.43

Full DLK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DLK2 p.Ala19Thr Uncertain significance ★ ⚠ same type
DLK2 p.Ala19Val Uncertain significance ★ ⚠ same type
DLK2 p.Arg143Cys Uncertain significance ★ ⚠ same type
DLK2 p.Arg59His Uncertain significance ★ ⚠ same type
DLK2 p.Asp27Asn Uncertain significance ★ ⚠ same type
DLK2 p.Asp43Glu Uncertain significance ★ same type
DLK2 p.Cys117Tyr Uncertain significance ★ ⚠ same type
DLK2 p.Glu114Gly 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/dlk2-p-pro23arg (accessed [today's date]).

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