Is HELLS p.His345= (c.1035T>C) pathogenic?

HELLS p.His345= (c.1035T>C) is classified Conflicting classifications of pathogenicity in HELLS (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-23). Very rare (popmax 0.00696%, afr); Associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4.

What condition is associated with HELLS p.His345= (c.1035T>C)?

HELLS p.His345= (c.1035T>C) is associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4 (ClinVar).

How common is HELLS p.His345= (c.1035T>C) in the general population?

HELLS p.His345= (c.1035T>C) is very rare (popmax 0.00696%, afr) (gnomAD).

HELLS p.His345=

c.1035T>C · rs773771433 · VCV2969713

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00696%, afr)

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
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.9	GERP 1.9, phastCons 1
Overall
CADD	13.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00696% African / African-American · 5/71,788 alleles

Filtering AF 0.00273% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00178%

Overall 0.000327% 5/1,527,164 alleles · very rare exomes 2/1,374,948 · genomes 3/152,216 · 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.His345=
Coding: c.1035T>C
MANE Select: NM_018063
dbSNP: rs773771433
Type: single nucleotide variant
Location: chr10:94581328 (GRCh38)
Gene constraint: LOEUF 0.587 · pLI 0.63 (gnomAD)
Structure: AlphaFold pLDDT 68.76 · 4 PDB
Residue 345: the helicase atp-binding 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 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
HELLS p.Glu655= 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-his345 (accessed [today's date]).

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