Is DLK2 p.Arg195Ser (c.583C>A) pathogenic?

DLK2 p.Arg195Ser (c.583C>A) is classified Uncertain significance in DLK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: ambiguous (0.4393); Very rare (popmax 0.00153%, nfe).

How common is DLK2 p.Arg195Ser (c.583C>A) in the general population?

DLK2 p.Arg195Ser (c.583C>A) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about DLK2 p.Arg195Ser (c.583C>A)?

AlphaMissense predicts ambiguous (score 0.4393) — an in-silico prediction, not a clinical call.

DLK2 p.Arg195Ser

c.583C>A · rs370997475 · VCV2229127

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4393 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4393	ambiguous
REVEL	0.615	indeterminate
SaProt	LLR -5.29	tolerated
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP -1.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 4,283 bp · p 1.3e-09 · regional, not allelic
Overall
CADD	29.5	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 0.00153% European (non-Finnish) · 18/1,180,038 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00123% 18/1,461,886 alleles · very rare

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.Arg195Ser
Coding: c.583C>A
MANE Select: NM_001198934 · reported on NM_023932
dbSNP: rs370997475
Type: single nucleotide variant
Location: chr6:43451108 (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-arg195ser (accessed [today's date]).

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