Is CUL7 p.Pro246Ser (c.736C>T) pathogenic?

CUL7 p.Pro246Ser (c.736C>T) is classified Uncertain significance in CUL7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-08). AlphaMissense: ambiguous (0.4722); Ultra-rare (popmax 0.0147%, afr); Associated with Inborn genetic diseases.

What condition is associated with CUL7 p.Pro246Ser (c.736C>T)?

CUL7 p.Pro246Ser (c.736C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CUL7 p.Pro246Ser (c.736C>T) in the general population?

CUL7 p.Pro246Ser (c.736C>T) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about CUL7 p.Pro246Ser (c.736C>T)?

AlphaMissense predicts ambiguous (score 0.4722) — an in-silico prediction, not a clinical call.

CUL7 p.Pro246Ser

c.736C>T · VCV3837467

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4722 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4722	ambiguous
REVEL	0.815	moderately pathogenic-leaning
SaProt	LLR -1.65	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 3,236 bp · p 0.0073 · regional, not allelic
Overall
CADD	26.1	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 0.0147% African / African-American · 11/75,018 alleles

Filtering AF 0.00814% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00124% 20/1,613,926 alleles · ultra-rare exomes 20/1,461,720 · genomes 0/152,206 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,820
Remaining individualsnot grpmax-eligible	0.0048%	20,834
South Asian	0.00439%	22,761
Admixed American	0.00167%	60,006
European (non-Finnish)	8.47e-05%	1,180,006

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.Pro246Ser
Coding: c.736C>T
MANE Select: NM_014780
Type: single nucleotide variant
Location: chr6:43051465 (GRCh38)
Gene constraint: LOEUF 0.62 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.11 · 2 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CUL7 p.Pro246Leu Uncertain significance ★ ⚠ same residue
CUL7 c.2660+1G>C Pathogenic ★★ same condition
CUL7 p.Ala272Val Uncertain significance ★★ ⚠ same condition
CUL7 p.Ala993Val Uncertain significance ★★ ⚠ same condition
CUL7 p.Arg1085Cys Uncertain significance ★★ ⚠ same condition
CUL7 p.Arg1094Cys Uncertain significance ★★ ⚠ same condition
CUL7 p.Arg1145Cys Uncertain significance ★★ ⚠ same condition
CUL7 p.Arg1190Trp Uncertain significance ★★ ⚠ same condition

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-pro246ser (accessed [today's date]).

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