Is HELLS p.Thr663= (c.1989G>A) pathogenic?

HELLS p.Thr663= (c.1989G>A) is classified Benign/Likely benign in HELLS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-24). Rare (popmax 0.635%, eas).

How common is HELLS p.Thr663= (c.1989G>A) in the general population?

HELLS p.Thr663= (c.1989G>A) is rare (popmax 0.635%, eas) (gnomAD).

HELLS p.Thr663=

c.1989G>A · rs144657635 · VCV798889

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.635%, eas)

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 1.9	GERP -1.9, phastCons 0.99
Overall
CADD	5.686	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.635% East Asian · 285/44,848 alleles

Filtering AF 0.575% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.551%

Overall 0.0212% 342/1,611,808 alleles · rare exomes 286/1,459,614 · genomes 56/152,194 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.635%	157
Remaining individualsnot grpmax-eligible	0.0192%	5,202
Admixed American	0.0133%	7,501
South Asian	0.00769%	13,007
African / African-American	0.00534%	18,740
European (non-Finnish)	0.00221%	45,307

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.Thr663=
Coding: c.1989G>A
MANE Select: NM_018063
dbSNP: rs144657635
Type: single nucleotide variant
Location: chr10:94593516 (GRCh38)
Gene constraint: LOEUF 0.587 · pLI 0.63 (gnomAD)
Structure: AlphaFold pLDDT 68.76 · 4 PDB
Residue 663: the helicase c-terminal domain

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

Similar variants

HELLS p.Thr663Met Conflicting classifications of pathogenicity ★ ⚠ 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-thr663 (accessed [today's date]).

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