Is CUL7 p.Pro663Leu (c.1988C>T) pathogenic?

CUL7 p.Pro663Leu (c.1988C>T) is classified Uncertain significance in CUL7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-20). AlphaMissense: likely benign (0.2178); Very rare (popmax 0.00659%, sas); Associated with Inborn genetic diseases.

What condition is associated with CUL7 p.Pro663Leu (c.1988C>T)?

CUL7 p.Pro663Leu (c.1988C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CUL7 p.Pro663Leu (c.1988C>T) in the general population?

CUL7 p.Pro663Leu (c.1988C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about CUL7 p.Pro663Leu (c.1988C>T)?

AlphaMissense predicts likely benign (score 0.2178) — an in-silico prediction, not a clinical call.

CUL7 p.Pro663Leu

c.1988C>T · rs754005929 · VCV3078969

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2178 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2178	likely benign
REVEL	0.274	benign-leaning
SaProt	LLR -8.46	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 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 11 kb · p 6.7e-07 · regional, not allelic
Overall
CADD	26.4	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 0.00659% South Asian · 6/91,056 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00217% 35/1,612,994 alleles · very rare exomes 32/1,460,860 · genomes 3/152,134 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,176
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
Remaining individualsnot grpmax-eligible	0.0032%	31,222
African / African-American	0.00267%	37,444
European (non-Finnish)	0.00195%	51,266
Admixed American	0.00167%	60,002

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.Pro663Leu
Coding: c.1988C>T
MANE Select: NM_014780
dbSNP: rs754005929
Type: single nucleotide variant
Location: chr6:43048407 (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.Pro663= Likely benign ★★ 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-pro663leu (accessed [today's date]).

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