Is DLK2 p.Pro377Ser (c.1129C>T) pathogenic?

DLK2 p.Pro377Ser (c.1129C>T) is classified Uncertain significance in DLK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely benign (0.0874); Very rare (popmax 0.00277%, nfe).

How common is DLK2 p.Pro377Ser (c.1129C>T) in the general population?

DLK2 p.Pro377Ser (c.1129C>T) is very rare (popmax 0.00277%, nfe) (gnomAD).

What do computational predictors say about DLK2 p.Pro377Ser (c.1129C>T)?

AlphaMissense predicts likely benign (score 0.0874) — an in-silico prediction, not a clinical call.

DLK2 p.Pro377Ser

c.1129C>T · VCV4241191

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0874 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00277%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0874	likely benign
REVEL	0.352	indeterminate
SaProt	LLR -7.60	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 4.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 4,283 bp · p 1.3e-09 · regional, not allelic
Overall
CADD	22.8	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 0.00277% European (non-Finnish) · 32/1,156,480 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00171%

Overall 0.00204% 32/1,569,760 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.Pro377Ser
Coding: c.1129C>T
MANE Select: NM_001198934 · reported on NM_023932
Type: single nucleotide variant
Location: chr6:43450562 (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-pro377ser (accessed [today's date]).

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