Is ULK2 p.Pro449Ser (c.1345C>T) pathogenic?

ULK2 p.Pro449Ser (c.1345C>T) is classified Uncertain significance in ULK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-29). AlphaMissense: likely benign (0.0696); Ultra-rare (popmax 0.0201%, eas).

How common is ULK2 p.Pro449Ser (c.1345C>T) in the general population?

ULK2 p.Pro449Ser (c.1345C>T) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

What do computational predictors say about ULK2 p.Pro449Ser (c.1345C>T)?

AlphaMissense predicts likely benign (score 0.0696) — an in-silico prediction, not a clinical call.

ULK2 p.Pro449Ser

c.1345C>T · rs201765692 · VCV2603175

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0696 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0696	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -5.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.9	GERP -1.9, phastCons 0.16
Regional constraint	o/e 0.94	unconstrained · MANE · 50 kb · p 0.065 · regional, not allelic
Overall
CADD	11.34	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 0.0201% East Asian · 9/44,886 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00779%

Overall 0.00254% 41/1,614,066 alleles · ultra-rare exomes 40/1,461,706 · genomes 1/152,360 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0201%	4,987
Remaining individualsnot grpmax-eligible	0.0048%	20,834
European (non-Finnish)	0.00246%	40,689

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.Pro449Ser
Coding: c.1345C>T
MANE Select: NM_014683
dbSNP: rs201765692
Type: single nucleotide variant
Location: chr17:19801873 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.32 · 5 PDB
Residue 449: the 'disordered' region

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

Similar variants

ULK2 p.Pro449Leu Likely benign ★ same residue
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

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-pro449ser (accessed [today's date]).

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