Is ULK4 p.Val686Ile (c.2056G>A) pathogenic?

ULK4 p.Val686Ile (c.2056G>A) is classified Likely benign in ULK4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-03-01). AlphaMissense: likely benign (0.1196); Rare (popmax 0.499%, nfe); Associated with Moderate intellectual disability.

What condition is associated with ULK4 p.Val686Ile (c.2056G>A)?

ULK4 p.Val686Ile (c.2056G>A) is associated with Moderate intellectual disability (ClinVar).

How common is ULK4 p.Val686Ile (c.2056G>A) in the general population?

ULK4 p.Val686Ile (c.2056G>A) is rare (popmax 0.499%, nfe) (gnomAD).

What do computational predictors say about ULK4 p.Val686Ile (c.2056G>A)?

AlphaMissense predicts likely benign (score 0.1196) — an in-silico prediction, not a clinical call.

ULK4 p.Val686Ile

c.2056G>A · rs77615850 · VCV224082

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1196 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.499%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Moderate intellectual disability

Computational evidence

Protein change
AlphaMissense	0.1196	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -5.74	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 5.9	GERP 0.98, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 708 kb · p 0.038 · regional, not allelic
Overall
CADD	23.2	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 0.499% European (non-Finnish) · 5,892/1,179,706 alleles

Filtering AF 0.489% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.484%

Overall 0.432% 6,963/1,613,304 alleles · rare exomes 6,376/1,461,020 · genomes 587/152,284 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	2.63%	38
Finnishnot grpmax-eligible	0.539%	186
European (non-Finnish)grpmax	0.499%	200
Remaining individualsnot grpmax-eligible	0.432%	231
Admixed American	0.302%	331
Ashkenazi Jewishnot grpmax-eligible	0.213%	469
South Asian	0.124%	805
African / African-American	0.0947%	1,056
Middle Eastern	0.0495%	2,019
East Asian	0.00223%	44,788

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val686Ile
Coding: c.2056G>A
MANE Select: NM_017886
dbSNP: rs77615850
Type: single nucleotide variant
Location: chr3:41789798 (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

Disease context

Moderate intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ULK4 p.Arg862Ter Likely benign ★ same condition
ULK4 p.Val963Met Likely benign ★ same condition
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

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-val686ile (accessed [today's date]).

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