Is CUL7 p.Pro861Ser (c.2581C>T) pathogenic?

CUL7 p.Pro861Ser (c.2581C>T) is classified Conflicting classifications of pathogenicity in CUL7 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-24). AlphaMissense: likely benign (0.2184); Rare (popmax 0.272%, sas).

How common is CUL7 p.Pro861Ser (c.2581C>T) in the general population?

CUL7 p.Pro861Ser (c.2581C>T) is rare (popmax 0.272%, sas) (gnomAD).

What do computational predictors say about CUL7 p.Pro861Ser (c.2581C>T)?

AlphaMissense predicts likely benign (score 0.2184) — an in-silico prediction, not a clinical call.

CUL7 p.Pro861Ser

c.2581C>T · rs147452416 · VCV631982

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2184 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.272%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2184	likely benign
REVEL	0.534	indeterminate
SaProt	LLR -7.63	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.7, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 11 kb · p 6.7e-07 · regional, not allelic
Overall
CADD	23.1	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 0.272% South Asian · 248/91,088 alleles

Filtering AF 0.244% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.234%

Overall 0.0174% 281/1,614,228 alleles · rare exomes 269/1,461,858 · genomes 12/152,370 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.272%	367
Middle Eastern	0.0497%	2,011
Remaining individualsnot grpmax-eligible	0.016%	6,250
African / African-American	0.004%	25,021
East Asian	0.00223%	44,888
European (non-Finnish)	0.00136%	73,753

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: CUL7
Protein: p.Pro861Ser
Coding: c.2581C>T
MANE Select: NM_014780
dbSNP: rs147452416
Type: single nucleotide variant
Location: chr6:43046315 (GRCh38)
Gene constraint: LOEUF 0.62 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.11 · 2 PDB
Residue 861: the doc domain

Full CUL7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CUL7 p.Pro861= Uncertain significance ★ same residue
CUL7 c.2397+1G>A Likely pathogenic ★★ same type
CUL7 c.2398-2A>G Likely pathogenic ★★ same type
CUL7 c.2660+1G>C Pathogenic ★★ same type
CUL7 c.3356-2A>C Likely pathogenic ★★ same type
CUL7 p.Arg1440Ter Pathogenic/Likely pathogenic ★★ same type
CUL7 p.Arg1445Ter Pathogenic ★★ same type
CUL7 p.Arg1573Ter Pathogenic ★★ 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/cul7-p-pro861ser (accessed [today's date]).

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