Is ULK4 p.Ile554Val (c.1660A>G) pathogenic?

ULK4 p.Ile554Val (c.1660A>G) is classified Uncertain significance in ULK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely benign (0.0644); Ultra-rare (popmax 0.0732%, afr).

How common is ULK4 p.Ile554Val (c.1660A>G) in the general population?

ULK4 p.Ile554Val (c.1660A>G) is ultra-rare (popmax 0.0732%, afr) (gnomAD).

What do computational predictors say about ULK4 p.Ile554Val (c.1660A>G)?

AlphaMissense predicts likely benign (score 0.0644) — an in-silico prediction, not a clinical call.

ULK4 p.Ile554Val

c.1660A>G · rs375588484 · VCV3186374

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0644 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0732%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0644	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -7.25	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 0.55	GERP -0.37, phastCons 0.4
Regional constraint	o/e 1.05	unconstrained · MANE · 708 kb · p 0.038 · regional, not allelic
Overall
CADD	14.78	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 0.0732% African / African-American · 48/65,534 alleles

Filtering AF 0.0567% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0509%

Overall 0.00453% 71/1,566,970 alleles · ultra-rare exomes 43/1,423,452 · genomes 28/143,518 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0732%	1,365
Middle Eastern	0.0171%	5,842
Admixed American	0.0125%	8,030
South Asian	0.00347%	28,820
Remaining individualsnot grpmax-eligible	0.0033%	30,341
European (non-Finnish)	0.000866%	115,485

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.Ile554Val
Coding: c.1660A>G
MANE Select: NM_017886
dbSNP: rs375588484
Type: single nucleotide variant
Location: chr3:41835968 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.59 · 2 PDB

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-ile554val (accessed [today's date]).

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