Is CUL7 p.His705= (c.2115C>T) pathogenic?

CUL7 p.His705= (c.2115C>T) is classified Conflicting classifications of pathogenicity in CUL7 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-09). Rare (popmax 0.247%, mid); Associated with 3M syndrome 1.

What condition is associated with CUL7 p.His705= (c.2115C>T)?

CUL7 p.His705= (c.2115C>T) is associated with 3M syndrome 1 (ClinVar).

How common is CUL7 p.His705= (c.2115C>T) in the general population?

CUL7 p.His705= (c.2115C>T) is rare (popmax 0.247%, mid) (gnomAD).

CUL7 p.His705=

c.2115C>T · rs143128153 · VCV356843

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.247%, mid)

Conditions

3M syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -9.1	GERP -3.4
Overall
CADD	0.517	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.247% Middle Eastern · 15/6,062 alleles

Filtering AF 0.189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.178%

Overall 0.0364% 587/1,614,102 alleles · rare exomes 437/1,461,808 · genomes 150/152,294 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.247%	404
Admixed American	0.22%	455
African / African-American	0.2%	500
Remaining individualsnot grpmax-eligible	0.0784%	1,275
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,289
European (non-Finnish)	0.019%	5,268
South Asian	0.00769%	13,012
East Asian	0.00223%	44,880

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.His705=
Coding: c.2115C>T
MANE Select: NM_014780
dbSNP: rs143128153
Type: single nucleotide variant
Location: chr6:43048202 (GRCh38)
Gene constraint: LOEUF 0.62 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.11 · 2 PDB
Residue 705: 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-his705 (accessed [today's date]).

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