Is ULK4 p.Ala671Asp (c.2012C>A) pathogenic?

ULK4 p.Ala671Asp (c.2012C>A) is classified Uncertain significance in ULK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-12). AlphaMissense: likely pathogenic (0.9728); Very rare (popmax 0.00171%, amr).

How common is ULK4 p.Ala671Asp (c.2012C>A) in the general population?

ULK4 p.Ala671Asp (c.2012C>A) is very rare (popmax 0.00171%, amr) (gnomAD).

What do computational predictors say about ULK4 p.Ala671Asp (c.2012C>A)?

AlphaMissense predicts likely pathogenic (score 0.9728) — an in-silico prediction, not a clinical call.

ULK4 p.Ala671Asp

c.2012C>A · VCV4602014

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9728 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00171%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9728	likely pathogenic · top 1% in ULK4
REVEL	0.594	indeterminate
SaProt	LLR -15.30	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 708 kb · p 0.038 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00171% Admixed American · 1/58,378 alleles

Overall 0.000125% 2/1,603,250 alleles · very rare exomes 2/1,451,010 · genomes 0/152,240 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00171%	58,378
Remaining individualsnot grpmax-eligible	0.00161%	62,054

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.Ala671Asp
Coding: c.2012C>A
MANE Select: NM_017886
Type: single nucleotide variant
Location: chr3:41789842 (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-ala671asp (accessed [today's date]).

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