Is HELLS p.Arg721Cys (c.2161C>T) pathogenic?

HELLS p.Arg721Cys (c.2161C>T) is classified Uncertain significance in HELLS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-13). AlphaMissense: likely pathogenic (0.8471); Very rare (popmax 0.00585%, nfe); Associated with Inborn genetic diseases.

What condition is associated with HELLS p.Arg721Cys (c.2161C>T)?

HELLS p.Arg721Cys (c.2161C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HELLS p.Arg721Cys (c.2161C>T) in the general population?

HELLS p.Arg721Cys (c.2161C>T) is very rare (popmax 0.00585%, nfe) (gnomAD).

What do computational predictors say about HELLS p.Arg721Cys (c.2161C>T)?

AlphaMissense predicts likely pathogenic (score 0.8471) — an in-silico prediction, not a clinical call.

HELLS p.Arg721Cys

c.2161C>T · rs371792267 · VCV1896244

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8471 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00585%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8471	likely pathogenic
REVEL	0.901	moderately pathogenic-leaning
SaProt	LLR -15.22	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.28	constrained · MANE · 1,268 bp · p 2.1e-10 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00585% European (non-Finnish) · 69/1,179,536 alleles

Filtering AF 0.0047% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00431%

Overall 0.00452% 73/1,613,448 alleles · very rare exomes 71/1,461,304 · genomes 2/152,144 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00585%	17,095
Finnishnot grpmax-eligible	0.00312%	32,013
South Asian	0.0022%	45,531

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.Arg721Cys
Coding: c.2161C>T
MANE Select: NM_018063
dbSNP: rs371792267
Type: single nucleotide variant
Location: chr10:94594767 (GRCh38)
Gene constraint: LOEUF 0.587 · pLI 0.63 (gnomAD)
Structure: AlphaFold pLDDT 68.76 · 4 PDB
Residue 721: the helicase c-terminal domain

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
HELLS p.Arg319Trp Uncertain significance ★★ ⚠ same condition
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.Asp117Gly Uncertain significance ★★ ⚠ same condition
HELLS p.Asp523Val 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-arg721cys (accessed [today's date]).

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