Is HELLS p.Glu232Gln (c.694G>C) pathogenic?

HELLS p.Glu232Gln (c.694G>C) is classified Uncertain significance in HELLS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: ambiguous (0.5345); Very rare (popmax 8.52e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with HELLS p.Glu232Gln (c.694G>C)?

HELLS p.Glu232Gln (c.694G>C) is associated with Inborn genetic diseases (ClinVar).

How common is HELLS p.Glu232Gln (c.694G>C) in the general population?

HELLS p.Glu232Gln (c.694G>C) is very rare (popmax 8.52e-05%, nfe) (gnomAD).

What do computational predictors say about HELLS p.Glu232Gln (c.694G>C)?

AlphaMissense predicts ambiguous (score 0.5345) — an in-silico prediction, not a clinical call.

HELLS p.Glu232Gln

c.694G>C · VCV4621413

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5345 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.52e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5345	ambiguous
REVEL	0.782	moderately pathogenic-leaning
SaProt	LLR -8.00	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.76 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 583 bp · p 5.4e-11 · regional, not allelic
Overall
CADD	28.9	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 8.52e-05% European (non-Finnish) · 1/1,173,074 alleles

Overall 6.22e-05% 1/1,606,454 alleles · very rare exomes 1/1,454,204 · genomes 0/152,250 · 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
Protein: p.Glu232Gln
Coding: c.694G>C
MANE Select: NM_018063
Type: single nucleotide variant
Location: chr10:94574176 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HELLS p.Ala16Pro Uncertain significance ★★ ⚠ same condition
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HELLS p.Arg507Gln Uncertain significance ★★ ⚠ same condition
HELLS p.Arg541Gln Uncertain significance ★★ ⚠ same condition
HELLS p.Arg5Trp Uncertain significance ★★ ⚠ same condition
HELLS p.Arg66Cys Uncertain significance ★★ ⚠ same condition
HELLS p.Arg721Cys Uncertain significance ★★ ⚠ same condition
HELLS p.Asp117Gly 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/hells-p-glu232gln (accessed [today's date]).

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