Is DLK2 p.Arg170Pro (c.509G>C) pathogenic?

DLK2 p.Arg170Pro (c.509G>C) is classified Uncertain significance in DLK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: likely pathogenic (0.7697); Very rare (popmax 8.47e-05%, nfe).

How common is DLK2 p.Arg170Pro (c.509G>C) in the general population?

DLK2 p.Arg170Pro (c.509G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about DLK2 p.Arg170Pro (c.509G>C)?

AlphaMissense predicts likely pathogenic (score 0.7697) — an in-silico prediction, not a clinical call.

DLK2 p.Arg170Pro

c.509G>C · VCV4241195

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7697 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.7697	likely pathogenic
REVEL	0.51	indeterminate
SaProt	LLR -14.82	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -4.7	GERP -3.9
Regional constraint	o/e 0.74	unconstrained · MANE · 4,283 bp · p 1.3e-09 · regional, not allelic
Overall
CADD	17.62	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.47e-05% European (non-Finnish) · 1/1,180,022 alleles

Overall 6.2e-05% 1/1,614,154 alleles · very rare exomes 1/1,461,870 · genomes 0/152,284 · joint denominator

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.Arg170Pro
Coding: c.509G>C
MANE Select: NM_023932
Type: single nucleotide variant
Location: chr6:43451182 (GRCh38)

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

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-arg170pro (accessed [today's date]).

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