Is CUL4A p.Ser516Asn (c.1547G>A) pathogenic?

CUL4A p.Ser516Asn (c.1547G>A) is classified Uncertain significance in CUL4A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: likely benign (0.064); Very rare (popmax 0.00223%, eas).

How common is CUL4A p.Ser516Asn (c.1547G>A) in the general population?

CUL4A p.Ser516Asn (c.1547G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CUL4A p.Ser516Asn (c.1547G>A)?

AlphaMissense predicts likely benign (score 0.064) — an in-silico prediction, not a clinical call.

CUL4A p.Ser516Asn

c.1547G>A · VCV4008333

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.064 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.064	likely benign
REVEL	0.167	moderately benign-leaning
SaProt	LLR -7.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.67, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 7,912 bp · p 0.00028 · regional, not allelic
Overall
CADD	21.7	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 0.00223% East Asian · 1/44,870 alleles

Overall 6.84e-05% 1/1,460,996 alleles · very rare

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: CUL4A
Protein: p.Ser516Asn
Coding: c.1547G>A
MANE Select: NM_001008895
Type: single nucleotide variant
Location: chr13:113245972 (GRCh38)
Gene constraint: LOEUF 0.324 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.26 · 20 PDB
Residue 516: a turn

Full CUL4A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CUL4A p.Ala13Pro Uncertain significance ★ ⚠ same type
CUL4A p.Ala208Val Uncertain significance ★ ⚠ same type
CUL4A p.Ala486Thr Uncertain significance ★ ⚠ same type
CUL4A p.Arg144Gly Uncertain significance ★ ⚠ same type
CUL4A p.Arg385Gln Uncertain significance ★ ⚠ same type
CUL4A p.Arg49Gln Uncertain significance ★ ⚠ same type
CUL4A p.Arg80Lys Uncertain significance ★ ⚠ same type
CUL4A p.Asn603Ser Uncertain significance ★ ⚠ 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/cul4a-p-ser516asn (accessed [today's date]).

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