Is HELLS p.Arg510Ter (c.1528C>T) pathogenic?

HELLS p.Arg510Ter (c.1528C>T) is classified Pathogenic in HELLS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-22). Very rare (popmax 8.48e-05%, nfe).

How common is HELLS p.Arg510Ter (c.1528C>T) in the general population?

HELLS p.Arg510Ter (c.1528C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

HELLS p.Arg510Ter

c.1528C>T · rs2493269726 · VCV2796027

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 14 of 22
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.7, phastCons 1
Overall
CADD	40.0	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 8.48e-05% European (non-Finnish) · 1/1,179,120 alleles

Overall 6.21e-05% 1/1,609,754 alleles · very rare exomes 1/1,457,604 · genomes 0/152,150 · 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.Arg510Ter
Coding: c.1528C>T
MANE Select: NM_018063
dbSNP: rs2493269726
Type: single nucleotide variant
Location: chr10:94590452 (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 p.Arg510Gln Uncertain significance ★ ⚠ same residue
HELLS p.Arg510Leu Uncertain significance ★ ⚠ same residue
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

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-arg510ter (accessed [today's date]).

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