Is ULK4 p.Ser640Ala (c.1918T>G) pathogenic?

ULK4 p.Ser640Ala (c.1918T>G) is classified Benign in ULK4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2016-03-29). AlphaMissense: likely benign (0.0484); Common (popmax 97.3%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ULK4 p.Ser640Ala (c.1918T>G)?

AlphaMissense predicts likely benign (score 0.0484) — an in-silico prediction, not a clinical call.

ULK4 p.Ser640Ala

Q: How common is ULK4 p.Ser640Ala (c.1918T>G) in the general population?

ULK4 p.Ser640Ala (c.1918T>G) is common (popmax 97.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1918T>G · rs4973986 · VCV403583

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0484 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 97.3%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0484	likely benign
REVEL	0.19	benign-leaning
SaProt	LLR -4.92	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 4.7	GERP 0.86, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 708 kb · p 0.038 · regional, not allelic
Overall
CADD	16.69	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 97.3% African / African-American · 72,938/75,000 alleles

Filtering AF 96.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 96.4%

Overall 84.4% 1,361,936/1,613,390 alleles · common exomes 1,229,387/1,461,292 · genomes 132,549/152,098 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	97.3%	1
Admixed American	91.8%	1
Middle Eastern	89.4%	1
Ashkenazi Jewishnot grpmax-eligible	89.3%	1
Remaining individualsnot grpmax-eligible	84.6%	1
South Asian	84.3%	1
European (non-Finnish)	83.6%	1
East Asian	79.9%	1
Finnishnot grpmax-eligible	77.9%	1
Amishnot grpmax-eligible	63.7%	2

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.Ser640Ala
Coding: c.1918T>G
MANE Select: NM_017886
dbSNP: rs4973986
Type: single nucleotide variant
Location: chr3:41800224 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.59 · 2 PDB
Residue 640: a UniProt-annotated variant site (in)

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-ser640ala (accessed [today's date]).

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