Is ULK3 p.Arg258Cys (c.772C>T) pathogenic?

ULK3 p.Arg258Cys (c.772C>T) is classified Uncertain significance in ULK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-25). AlphaMissense: likely pathogenic (0.912); Very rare (popmax 0.00722%, eas).

How common is ULK3 p.Arg258Cys (c.772C>T) in the general population?

ULK3 p.Arg258Cys (c.772C>T) is very rare (popmax 0.00722%, eas) (gnomAD).

What do computational predictors say about ULK3 p.Arg258Cys (c.772C>T)?

AlphaMissense predicts likely pathogenic (score 0.912) — an in-silico prediction, not a clinical call.

ULK3 p.Arg258Cys

c.772C>T · VCV4830132

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.912 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00722%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.912	likely pathogenic
REVEL	0.8	moderately pathogenic-leaning
SaProt	LLR -12.21	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 5,874 bp · p 0.0054 · regional, not allelic
Overall
CADD	33.0	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 0.00722% East Asian · 3/41,528 alleles

Filtering AF 0.00192% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00103%

Overall 0.000386% 6/1,555,748 alleles · very rare exomes 6/1,403,462 · genomes 0/152,286 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00722%	13,843
European (non-Finnish)	0.000261%	383,712

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: ULK3
Protein: p.Arg258Cys
Coding: c.772C>T
MANE Select: NM_001099436
Type: single nucleotide variant
Location: chr15:74839638 (GRCh38)
Gene constraint: LOEUF 1.161 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.96 · 3 PDB
Residue 258: the protein kinase domain

Full ULK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ULK3 p.Arg101His Benign ★★ same type
ULK3 p.Pro177= Benign ★★ same type
ULK3 p.Ser468= Benign ★★ same type
ULK3 p.Ala114Val Uncertain significance ★ ⚠ same type
ULK3 p.Ala192Thr Uncertain significance ★ ⚠ same type
ULK3 p.Ala26Thr Uncertain significance ★ ⚠ same type
ULK3 p.Ala286Val Uncertain significance ★ ⚠ same type
ULK3 p.Ala303Thr 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/ulk3-p-arg258cys (accessed [today's date]).

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