Is ULK1 p.Ser593Phe (c.1778C>T) pathogenic?

ULK1 p.Ser593Phe (c.1778C>T) is classified Uncertain significance in ULK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-16). AlphaMissense: likely benign (0.0909); Very rare (popmax 0.005%, amr).

How common is ULK1 p.Ser593Phe (c.1778C>T) in the general population?

ULK1 p.Ser593Phe (c.1778C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about ULK1 p.Ser593Phe (c.1778C>T)?

AlphaMissense predicts likely benign (score 0.0909) — an in-silico prediction, not a clinical call.

ULK1 p.Ser593Phe

c.1778C>T · VCV3465809

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0909 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0909	likely benign
REVEL	0.121	moderately benign-leaning
SaProt	LLR -7.54	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 2.7	GERP -1.5, phastCons 0.48
Regional constraint	o/e 1.05	unconstrained · MANE · 6,947 bp · p 0.16 · regional, not allelic
Overall
CADD	11.91	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 0.005% Admixed American · 3/59,994 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000186% 3/1,612,524 alleles · very rare exomes 3/1,460,232 · genomes 0/152,292 · 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: ULK1
Protein: p.Ser593Phe
Coding: c.1778C>T
MANE Select: NM_003565
Type: single nucleotide variant
Location: chr12:131916059 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.99 · 19 PDB
Residue 593: the 'disordered' region

Full ULK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ULK1 p.Thr660Met Uncertain significance ★★ ⚠ same type
ULK1 p.Ala923= Benign ★★ same type
ULK1 p.Arg966= Benign ★★ same type
ULK1 p.Gly757= Benign ★★ same type
ULK1 p.Leu596= Benign ★★ same type
ULK1 p.Leu926= Benign ★★ same type
ULK1 p.Leu957= Benign/Likely benign ★★ same type
ULK1 p.Pro574= Benign/Likely benign ★★ 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/ulk1-p-ser593phe (accessed [today's date]).

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