Is ULK2 p.Ser522Leu (c.1565C>T) pathogenic?

ULK2 p.Ser522Leu (c.1565C>T) is classified Likely benign in ULK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). AlphaMissense: likely benign (0.0428); Ultra-rare (popmax 0.084%, mid).

How common is ULK2 p.Ser522Leu (c.1565C>T) in the general population?

ULK2 p.Ser522Leu (c.1565C>T) is ultra-rare (popmax 0.084%, mid) (gnomAD).

What do computational predictors say about ULK2 p.Ser522Leu (c.1565C>T)?

AlphaMissense predicts likely benign (score 0.0428) — an in-silico prediction, not a clinical call.

ULK2 p.Ser522Leu

c.1565C>T · rs540910964 · VCV2207222

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0428 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.084%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0428	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -6.78	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 4.5	GERP -0.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 50 kb · p 0.065 · regional, not allelic
Overall
CADD	15.23	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 0.084% Middle Eastern · 5/5,952 alleles

Filtering AF 0.0331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00584% 93/1,592,772 alleles · ultra-rare exomes 81/1,440,628 · genomes 12/152,144 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.084%	1,190
African / African-American	0.0148%	6,744
East Asian	0.0114%	8,802
Remaining individualsnot grpmax-eligible	0.0065%	15,386
European (non-Finnish)	0.00565%	17,708
Admixed American	0.00176%	56,818
Finnishnot grpmax-eligible	0.00157%	63,692

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.Ser522Leu
Coding: c.1565C>T
MANE Select: NM_014683
dbSNP: rs540910964
Type: single nucleotide variant
Location: chr17:19797640 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.32 · 5 PDB
Residue 522: the 'disordered' region

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-ser522leu (accessed [today's date]).

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