Is HELLS p.Glu818Ala (c.2453A>C) pathogenic?

HELLS p.Glu818Ala (c.2453A>C) is classified Uncertain significance in HELLS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). AlphaMissense: likely benign (0.138); Very rare (popmax 0.0045%, eas); Associated with Inborn genetic diseases.

What condition is associated with HELLS p.Glu818Ala (c.2453A>C)?

HELLS p.Glu818Ala (c.2453A>C) is associated with Inborn genetic diseases (ClinVar).

How common is HELLS p.Glu818Ala (c.2453A>C) in the general population?

HELLS p.Glu818Ala (c.2453A>C) is very rare (popmax 0.0045%, eas) (gnomAD).

What do computational predictors say about HELLS p.Glu818Ala (c.2453A>C)?

AlphaMissense predicts likely benign (score 0.138) — an in-silico prediction, not a clinical call.

HELLS p.Glu818Ala

c.2453A>C · rs774405443 · VCV3105076

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.138 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0045%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.138	likely benign
REVEL	0.496	indeterminate
SaProt	LLR -7.77	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 8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 6,790 bp · p 0.066 · regional, not allelic
Overall
CADD	22.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0045% East Asian · 2/44,460 alleles

Filtering AF 0.000746% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000279%

Overall 0.00019% 3/1,579,154 alleles · very rare exomes 2/1,426,976 · genomes 1/152,178 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0045%	22,230
Remaining individualsnot grpmax-eligible	0.00163%	61,292

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.Glu818Ala
Coding: c.2453A>C
MANE Select: NM_018063
dbSNP: rs774405443
Type: single nucleotide variant
Location: chr10:94601558 (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

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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
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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-glu818ala (accessed [today's date]).

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