Is HELLS p.Arg224Gln (c.671G>A) pathogenic?

HELLS p.Arg224Gln (c.671G>A) is classified Uncertain significance in HELLS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-20). AlphaMissense: ambiguous (0.5288); Ultra-rare (popmax 0.0164%, mid).

How common is HELLS p.Arg224Gln (c.671G>A) in the general population?

HELLS p.Arg224Gln (c.671G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about HELLS p.Arg224Gln (c.671G>A)?

AlphaMissense predicts ambiguous (score 0.5288) — an in-silico prediction, not a clinical call.

HELLS p.Arg224Gln

c.671G>A · rs1466354150 · VCV1385656

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5288 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5288	ambiguous
REVEL	0.841	moderately pathogenic-leaning
SaProt	LLR -9.02	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	33.0	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 0.0164% Middle Eastern · 1/6,080 alleles

Overall 0.000248% 4/1,613,650 alleles · ultra-rare exomes 3/1,461,500 · genomes 1/152,150 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
African / African-American	0.00133%	74,912
South Asian	0.0011%	91,078
European (non-Finnish)	8.48e-05%	1,179,722

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.Arg224Gln
Coding: c.671G>A
MANE Select: NM_018063
dbSNP: rs1466354150
Type: single nucleotide variant
Location: chr10:94574153 (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

Similar variants

HELLS c.370+2T>A Pathogenic ★★ same type
HELLS c.1488+4T>C Uncertain significance ★★ same type
HELLS p.Ala16Pro Uncertain significance ★★ ⚠ same type
HELLS p.Arg319Trp Uncertain significance ★★ ⚠ same type
HELLS p.Arg507Gln Uncertain significance ★★ ⚠ same type
HELLS p.Arg513Gly Uncertain significance ★★ ⚠ same type
HELLS p.Arg541Gln Uncertain significance ★★ ⚠ same type
HELLS p.Arg5Trp Uncertain significance ★★ ⚠ same type

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-arg224gln (accessed [today's date]).

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