Is HELLS p.Ile728Val (c.2182A>G) pathogenic?

HELLS p.Ile728Val (c.2182A>G) is classified Conflicting classifications of pathogenicity in HELLS (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0541); Rare (popmax 0.641%, afr); Associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4.

What condition is associated with HELLS p.Ile728Val (c.2182A>G)?

HELLS p.Ile728Val (c.2182A>G) is associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4 (ClinVar).

How common is HELLS p.Ile728Val (c.2182A>G) in the general population?

HELLS p.Ile728Val (c.2182A>G) is rare (popmax 0.641%, afr) (gnomAD).

What do computational predictors say about HELLS p.Ile728Val (c.2182A>G)?

AlphaMissense predicts likely benign (score 0.0541) — an in-silico prediction, not a clinical call.

HELLS p.Ile728Val

c.2182A>G · rs116043383 · VCV768380

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0541 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.641%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency-centromeric instability-facial anomalies syndrome 4

Computational evidence

Protein change
AlphaMissense	0.0541	likely benign
REVEL	0.185	benign-leaning
SaProt	LLR -5.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -3.3, phastCons 0.97
Regional constraint	o/e 0.28	constrained · MANE · 1,268 bp · p 2.1e-10 · regional, not allelic
Overall
CADD	10.8	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 0.641% African / African-American · 481/75,060 alleles

Filtering AF 0.593% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.575%

Overall 0.0362% 584/1,613,696 alleles · rare exomes 293/1,461,358 · genomes 291/152,338 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.641%	156
Middle Eastern	0.0825%	1,212
Admixed American	0.06%	1,667
Remaining individualsnot grpmax-eligible	0.0528%	1,894
European (non-Finnish)	0.00237%	42,128
South Asian	0.0011%	91,070

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.Ile728Val
Coding: c.2182A>G
MANE Select: NM_018063
dbSNP: rs116043383
Type: single nucleotide variant
Location: chr10:94594788 (GRCh38)
Gene constraint: LOEUF 0.587 · pLI 0.63 (gnomAD)
Structure: AlphaFold pLDDT 68.76 · 4 PDB
Residue 728: the helicase c-terminal domain

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 p.Ile728= Likely benign ★ same residue
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.31+20T>C Benign ★★ same condition
HELLS c.706-18A>G Likely benign ★★ same condition
HELLS p.Gln90= 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-p-ile728val (accessed [today's date]).

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