Is HELLS c.276+1G>A pathogenic?

HELLS c.276+1G>A is classified Likely pathogenic in HELLS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-19). Very rare (popmax 8.71e-05%, nfe); Associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4.

How common is HELLS c.276+1G>A in the general population?

HELLS c.276+1G>A is very rare (popmax 8.71e-05%, nfe) (gnomAD).

HELLS c.276+1G>A

Q: What condition is associated with HELLS c.276+1G>A?

HELLS c.276+1G>A is associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4 (ClinVar).

VCV3779727

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.71e-05%, nfe)

Conditions

immunodeficiency-centromeric instability-facial anomalies syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
Splicing
Splice region	donor +1	canonical splice dinucleotide (donor +1) · inside the BP7-excluded zone
SpliceAI	Δ0.99	donor loss · deltas
Pangolin	Δ0.82	loss · gain 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.71e-05% European (non-Finnish) · 1/1,147,934 alleles

Overall 6.51e-05% 1/1,537,052 alleles · very rare exomes 1/1,384,966 · genomes 0/152,086 · joint denominator

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
Coding: c.276+1G>A
MANE Select: NM_018063
Type: single nucleotide variant
Location: chr10:94554249 (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.Gln90= Benign ★★ same condition
HELLS p.Glu655= 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-c-276-plus-1g-a (accessed [today's date]).

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