Is CUL7 p.Leu1626Val (c.4876C>G) pathogenic?

CUL7 p.Leu1626Val (c.4876C>G) is classified Conflicting classifications of pathogenicity in CUL7 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-06). AlphaMissense: likely benign (0.1647); Rare (popmax 0.112%, eas); Associated with 3M syndrome 1.

What condition is associated with CUL7 p.Leu1626Val (c.4876C>G)?

CUL7 p.Leu1626Val (c.4876C>G) is associated with 3M syndrome 1 (ClinVar).

How common is CUL7 p.Leu1626Val (c.4876C>G) in the general population?

CUL7 p.Leu1626Val (c.4876C>G) is rare (popmax 0.112%, eas) (gnomAD).

What do computational predictors say about CUL7 p.Leu1626Val (c.4876C>G)?

AlphaMissense predicts likely benign (score 0.1647) — an in-silico prediction, not a clinical call.

CUL7 p.Leu1626Val

c.4876C>G · rs750060978 · VCV356817

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1647 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.112%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

3M syndrome 1

Computational evidence

Protein change
AlphaMissense	0.1647	likely benign
REVEL	0.507	indeterminate
SaProt	LLR -6.69	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 6	GERP 0.47, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 951 bp · p 0.37 · regional, not allelic
Overall
CADD	21.3	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 0.112% East Asian · 50/44,808 alleles

Filtering AF 0.0869% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0782%

Overall 0.00323% 52/1,611,566 alleles · rare exomes 46/1,459,454 · genomes 6/152,112 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.112%	896
Remaining individualsnot grpmax-eligible	0.00321%	31,162

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.Leu1626Val
Coding: c.4876C>G
MANE Select: NM_014780
dbSNP: rs750060978
Type: single nucleotide variant
Location: chr6:43037909 (GRCh38)
Gene constraint: LOEUF 0.62 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.11 · 2 PDB
Residue 1626: an α-helix

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

Disease context

3M syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CUL7 c.2397+1G>A Likely pathogenic ★★ same condition
CUL7 c.2660+1G>C Pathogenic ★★ same condition
CUL7 c.3356-2A>C Likely pathogenic ★★ same condition
CUL7 p.Arg1440Ter Pathogenic/Likely pathogenic ★★ same condition
CUL7 p.Arg1445Ter Pathogenic ★★ same condition
CUL7 p.Arg1573Ter Pathogenic ★★ same condition
CUL7 p.Arg382Ter Pathogenic ★★ same condition
CUL7 p.Arg550Ter Pathogenic/Likely pathogenic ★★ 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-leu1626val (accessed [today's date]).

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