Is CUL4A p.Ser78Phe (c.233C>T) pathogenic?

CUL4A p.Ser78Phe (c.233C>T) is classified Uncertain significance in CUL4A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). AlphaMissense: likely pathogenic (0.6562); Ultra-rare (popmax 0.0271%, sas).

How common is CUL4A p.Ser78Phe (c.233C>T) in the general population?

CUL4A p.Ser78Phe (c.233C>T) is ultra-rare (popmax 0.0271%, sas) (gnomAD).

What do computational predictors say about CUL4A p.Ser78Phe (c.233C>T)?

AlphaMissense predicts likely pathogenic (score 0.6562) — an in-silico prediction, not a clinical call.

CUL4A p.Ser78Phe

c.233C>T · VCV4657680

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6562 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0271%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6562	likely pathogenic
REVEL	0.453	indeterminate
SaProt	LLR -13.97	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 20 kb · p 0.2 · regional, not allelic
Overall
CADD	24.2	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 0.0271% South Asian · 22/81,108 alleles

Filtering AF 0.0183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0155%

Overall 0.00184% 28/1,518,432 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0271%	3,687
Remaining individualsnot grpmax-eligible	0.00342%	29,255
European (non-Finnish)	0.000353%	283,500

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.Ser78Phe
Coding: c.233C>T
MANE Select: NM_001008895
Type: single nucleotide variant
Location: chr13:113210057 (GRCh38)
Gene constraint: LOEUF 0.324 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.26 · 20 PDB
Residue 78: 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-ser78phe (accessed [today's date]).

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