Is ULK4 p.Cys141Phe (c.422G>T) pathogenic?

ULK4 p.Cys141Phe (c.422G>T) is classified Uncertain significance in ULK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-25). AlphaMissense: likely benign (0.2292); Ultra-rare (popmax 0.0508%, afr).

How common is ULK4 p.Cys141Phe (c.422G>T) in the general population?

ULK4 p.Cys141Phe (c.422G>T) is ultra-rare (popmax 0.0508%, afr) (gnomAD).

What do computational predictors say about ULK4 p.Cys141Phe (c.422G>T)?

AlphaMissense predicts likely benign (score 0.2292) — an in-silico prediction, not a clinical call.

ULK4 p.Cys141Phe

c.422G>T · VCV3465855

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2292 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0508%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2292	likely benign
REVEL	0.264	benign-leaning
SaProt	LLR -7.89	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 2.3	GERP 0.47, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 708 kb · p 0.038 · regional, not allelic
Overall
CADD	23.4	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 0.0508% African / African-American · 38/74,838 alleles

Filtering AF 0.038% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0335%

Overall 0.0026% 42/1,613,822 alleles · ultra-rare exomes 16/1,461,840 · genomes 26/151,982 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0508%	1,969
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)	0.000254%	393,332

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: ULK4
Protein: p.Cys141Phe
Coding: c.422G>T
MANE Select: NM_017886
Type: single nucleotide variant
Location: chr3:41931963 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.59 · 2 PDB
Residue 141: the protein kinase domain

Full ULK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ULK4 c.1183-8C>A Benign ★★ same type
ULK4 c.1288-9A>T Benign ★★ same type
ULK4 c.1349-5C>G Benign ★★ same type
ULK4 c.1577+10G>A Benign ★★ same type
ULK4 c.803+3A>C Benign ★★ same type
ULK4 p.Ala542Thr Benign ★★ same type
ULK4 p.Asn139Lys Likely benign ★★ ⚠ same type
ULK4 p.Ile224Val 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/ulk4-p-cys141phe (accessed [today's date]).

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