Is HELLS c.333+10C>G pathogenic?

HELLS c.333+10C>G is classified Likely benign in HELLS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-14). Ultra-rare (popmax 0.0209%, nfe).

How common is HELLS c.333+10C>G in the general population?

HELLS c.333+10C>G is ultra-rare (popmax 0.0209%, nfe) (gnomAD).

HELLS c.333+10C>G

rs370761610 · VCV1575767

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0209%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +10	near-intronic (+10 nt from the splice site)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.047	GERP -0.65
Non-coding constraint	Z -0.69	1 kb window · o/e 1.05 · regional · uncalibrated
Overall
CADD	9.28	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0209% European (non-Finnish) · 241/1,154,040 alleles

Filtering AF 0.0186% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.0175% 270/1,543,554 alleles · ultra-rare exomes 256/1,391,586 · genomes 14/151,968 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0387%	2,587
European (non-Finnish)grpmax	0.0209%	4,789
Finnishnot grpmax-eligible	0.00635%	15,744
Admixed American	0.00231%	43,354
South Asian	0.0013%	77,010

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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
Coding: c.333+10C>G
MANE Select: NM_018063
dbSNP: rs370761610
Type: single nucleotide variant
Location: chr10:94558205 (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-c-333-plus-10c-g (accessed [today's date]).

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