Is CUL4A p.Ser341Arg (c.1023C>A) pathogenic?

CUL4A p.Ser341Arg (c.1023C>A) is classified Uncertain significance in CUL4A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-26). AlphaMissense: likely pathogenic (0.601); Very rare (popmax 8.48e-05%, nfe).

How common is CUL4A p.Ser341Arg (c.1023C>A) in the general population?

CUL4A p.Ser341Arg (c.1023C>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CUL4A p.Ser341Arg (c.1023C>A)?

AlphaMissense predicts likely pathogenic (score 0.601) — an in-silico prediction, not a clinical call.

CUL4A p.Ser341Arg

c.1023C>A · VCV3498631

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.601 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.601	likely pathogenic
REVEL	0.178	moderately benign-leaning
SaProt	LLR -10.03	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.94 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.1	GERP -1.4, phastCons 0.001
Regional constraint	o/e 0.63	unconstrained · MANE · 11 kb · p 4.9e-09 · regional, not allelic
Overall
CADD	15.91	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 8.48e-05% European (non-Finnish) · 1/1,179,174 alleles

Overall 6.85e-05% 1/1,459,878 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.Ser341Arg
Coding: c.1023C>A
MANE Select: NM_001008895
Type: single nucleotide variant
Location: chr13:113239539 (GRCh38)
Gene constraint: LOEUF 0.324 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.26 · 20 PDB
Residue 341: an α-helix

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-ser341arg (accessed [today's date]).

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