HELLS c.31+20T>C

Q: Is HELLS c.31+20T>C pathogenic?

HELLS c.31+20T>C is classified Benign in HELLS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 77.6%, eas) — too common for a highly-penetrant pathogenic allele; Associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4.

Q: What condition is associated with HELLS c.31+20T>C?

HELLS c.31+20T>C is associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4 (ClinVar).

Q: How common is HELLS c.31+20T>C in the general population?

HELLS c.31+20T>C is common (popmax 77.6%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs10882474 · VCV1166855

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 77.6%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

immunodeficiency-centromeric instability-facial anomalies syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +20	near-intronic (+20 nt from the splice site)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.7	GERP -3.2
Non-coding constraint	Z 2.75	1 kb window · o/e 0.80 · regional · uncalibrated
Overall
CADD	5.55	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 77.6% East Asian · 32,079/41,356 alleles

Filtering AF 76.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 76.6%

Overall 45.9% 713,333/1,554,014 alleles · common exomes 640,958/1,402,136 · genomes 72,375/151,878 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	77.6%	1
South Asian	57.3%	2
African / African-American	56.2%	2
Remaining individualsnot grpmax-eligible	47.1%	2
European (non-Finnish)	44.2%	2
Amishnot grpmax-eligible	43.5%	2
Ashkenazi Jewishnot grpmax-eligible	42.4%	2
Middle Eastern	42.1%	2
Admixed American	37.2%	3
Finnishnot grpmax-eligible	36.8%	3

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.31+20T>C
MANE Select: NM_018063
dbSNP: rs10882474
Type: single nucleotide variant
Location: chr10:94545972 (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

immunodeficiency-centromeric instability-facial anomalies syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HELLS c.370+2T>A Pathogenic ★★ same condition
HELLS p.Arg513Gly Uncertain significance ★★ ⚠ same condition
HELLS p.Leu420Val Uncertain significance ★★ ⚠ same condition
HELLS c.153+10G>T Benign/Likely benign ★★ same condition
HELLS c.706-18A>G Likely benign ★★ same condition
HELLS p.Gln90= Benign ★★ same condition
HELLS p.Glu655= Benign ★★ same condition
HELLS p.Gly112Ser Benign/Likely benign ★★ 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-c-31-plus-20t-c (accessed [today's date]).

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