Is HELLS p.Thr724= (c.2172A>G) pathogenic?

HELLS p.Thr724= (c.2172A>G) is classified Likely benign in HELLS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-02). Ultra-rare (popmax 0.015%, amr).

How common is HELLS p.Thr724= (c.2172A>G) in the general population?

HELLS p.Thr724= (c.2172A>G) is ultra-rare (popmax 0.015%, amr) (gnomAD).

HELLS p.Thr724=

c.2172A>G · rs746276855 · VCV788676

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP 0.63, phastCons 1
Overall
CADD	8.822	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.015% Admixed American · 9/60,000 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00186% 30/1,613,762 alleles · ultra-rare exomes 28/1,461,540 · genomes 2/152,222 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,667
European (non-Finnish)	0.00178%	56,178

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.Thr724=
Coding: c.2172A>G
MANE Select: NM_018063
dbSNP: rs746276855
Type: single nucleotide variant
Location: chr10:94594778 (GRCh38)
Gene constraint: LOEUF 0.587 · pLI 0.63 (gnomAD)
Structure: AlphaFold pLDDT 68.76 · 4 PDB
Residue 724: the helicase c-terminal domain

Full HELLS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HELLS p.Thr724Ile Uncertain significance ★ ⚠ same residue
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

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-thr724 (accessed [today's date]).

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