Is HELLS p.Gln90= (c.270A>G) pathogenic?

HELLS p.Gln90= (c.270A>G) is classified Benign in HELLS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-02). Common (popmax 7.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4.

What condition is associated with HELLS p.Gln90= (c.270A>G)?

HELLS p.Gln90= (c.270A>G) is associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4 (ClinVar).

HELLS p.Gln90=

Q: How common is HELLS p.Gln90= (c.270A>G) in the general population?

HELLS p.Gln90= (c.270A>G) is common (popmax 7.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.270A>G · rs58643119 · VCV776529

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 7.3%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

immunodeficiency-centromeric instability-facial anomalies syndrome 4

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 -0.06	GERP -3.8, phastCons 0.005
Overall
CADD	2.649	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.3% African / African-American · 5,216/71,494 alleles

Filtering AF 7.13% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.06%

Overall 0.419% 6,555/1,562,744 alleles · common exomes 3,193/1,410,448 · genomes 3,362/152,296 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.3%	14
Middle Eastern	0.968%	103
Admixed American	0.801%	125
Remaining individualsnot grpmax-eligible	0.576%	174
Ashkenazi Jewishnot grpmax-eligible	0.122%	819
European (non-Finnish)	0.0455%	2,198
South Asian	0.0111%	9,019

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: HELLS
Protein: p.Gln90=
Coding: c.270A>G
MANE Select: NM_018063
dbSNP: rs58643119
Type: single nucleotide variant
Location: chr10:94554242 (GRCh38)
Gene constraint: LOEUF 0.587 · pLI 0.63 (gnomAD)
Structure: AlphaFold pLDDT 68.76 · 4 PDB

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

Disease context

immunodeficiency-centromeric instability-facial anomalies syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HELLS c.370+2T>A Pathogenic ★★ same condition
HELLS p.Arg513Gly Uncertain significance ★★ ⚠ same condition
HELLS p.Leu420Val Uncertain significance ★★ ⚠ same condition
HELLS c.153+10G>T Benign/Likely benign ★★ same condition
HELLS c.31+20T>C Benign ★★ same condition
HELLS c.706-18A>G Likely benign ★★ same condition
HELLS p.Glu655= Benign ★★ same condition
HELLS p.Gly112Ser Benign/Likely benign ★★ 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/hells-p-gln90 (accessed [today's date]).

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