Is ULK2 p.Pro219Leu (c.656C>T) pathogenic?

ULK2 p.Pro219Leu (c.656C>T) is classified Uncertain significance in ULK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely pathogenic (0.9618); Very rare (popmax 0.00138%, afr).

How common is ULK2 p.Pro219Leu (c.656C>T) in the general population?

ULK2 p.Pro219Leu (c.656C>T) is very rare (popmax 0.00138%, afr) (gnomAD).

What do computational predictors say about ULK2 p.Pro219Leu (c.656C>T)?

AlphaMissense predicts likely pathogenic (score 0.9618) — an in-silico prediction, not a clinical call.

ULK2 p.Pro219Leu

c.656C>T · VCV4601988

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9618 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00138%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9618	likely pathogenic
REVEL	0.534	indeterminate
SaProt	LLR -11.03	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 41 kb · p 1.7e-07 · regional, not allelic
Overall
CADD	29.9	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 0.00138% African / African-American · 1/72,310 alleles

Overall 6.32e-05% 1/1,583,424 alleles · very rare exomes 1/1,432,522 · genomes 0/150,902 · 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: ULK2
Protein: p.Pro219Leu
Coding: c.656C>T
MANE Select: NM_014683
Type: single nucleotide variant
Location: chr17:19841537 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.32 · 5 PDB
Residue 219: the protein kinase domain; an α-helix

Full ULK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ULK2 p.Arg881Gln Benign ★★ same type
ULK2 p.Gly5= Benign ★★ same type
ULK2 p.Lys539= Benign ★★ same type
ULK2 p.Tyr795= Benign ★★ same type
ULK2 p.His578Arg Likely pathogenic ★ ⚠ same type
ULK2 p.Ala1034Thr Uncertain significance ★ ⚠ same type
ULK2 p.Ala264Glu Uncertain significance ★ ⚠ same type
ULK2 p.Ala264Val 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/ulk2-p-pro219leu (accessed [today's date]).

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