Is HELLS p.Arg513Gly (c.1537A>G) pathogenic?

HELLS p.Arg513Gly (c.1537A>G) is classified Uncertain significance in HELLS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-08-10). AlphaMissense: likely benign (0.1478); Ultra-rare (popmax 0.0491%, nfe); Associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4.

What condition is associated with HELLS p.Arg513Gly (c.1537A>G)?

HELLS p.Arg513Gly (c.1537A>G) is associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4 (ClinVar).

How common is HELLS p.Arg513Gly (c.1537A>G) in the general population?

HELLS p.Arg513Gly (c.1537A>G) is ultra-rare (popmax 0.0491%, nfe) (gnomAD).

What do computational predictors say about HELLS p.Arg513Gly (c.1537A>G)?

AlphaMissense predicts likely benign (score 0.1478) — an in-silico prediction, not a clinical call.

HELLS p.Arg513Gly

c.1537A>G · rs145020994 · VCV1028083

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1478 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0491%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency-centromeric instability-facial anomalies syndrome 4

Computational evidence

Protein change
AlphaMissense	0.1478	likely benign
REVEL	0.764	pathogenic-leaning
SaProt	LLR -8.50	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 0.48, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 5,267 bp · p 2e-05 · regional, not allelic
Overall
CADD	24.7	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 0.0491% European (non-Finnish) · 579/1,179,564 alleles

Filtering AF 0.0458% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0444%

Overall 0.0371% 598/1,611,718 alleles · ultra-rare exomes 577/1,459,480 · genomes 21/152,238 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0491%	2,037
Remaining individualsnot grpmax-eligible	0.0192%	5,200
African / African-American	0.00668%	14,962
Admixed American	0.00337%	29,658

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.Arg513Gly
Coding: c.1537A>G
MANE Select: NM_018063
dbSNP: rs145020994
Type: single nucleotide variant
Location: chr10:94590461 (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.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
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-p-arg513gly (accessed [today's date]).

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