Is HELLS p.Pro609Leu (c.1826C>T) pathogenic?

HELLS p.Pro609Leu (c.1826C>T) is classified Uncertain significance in HELLS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-01). AlphaMissense: likely benign (0.1104); Very rare (popmax 0.00111%, sas).

How common is HELLS p.Pro609Leu (c.1826C>T) in the general population?

HELLS p.Pro609Leu (c.1826C>T) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about HELLS p.Pro609Leu (c.1826C>T)?

AlphaMissense predicts likely benign (score 0.1104) — an in-silico prediction, not a clinical call.

HELLS p.Pro609Leu

c.1826C>T · rs762107312 · VCV2013050

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1104 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1104	likely benign
REVEL	0.675	pathogenic-leaning
SaProt	LLR -12.54	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 0.95, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 5,267 bp · p 2e-05 · regional, not allelic
Overall
CADD	29.7	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 0.00111% South Asian · 1/90,476 alleles

Overall 6.21e-05% 1/1,610,764 alleles · very rare exomes 1/1,458,880 · genomes 0/151,884 · 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.Pro609Leu
Coding: c.1826C>T
MANE Select: NM_018063
dbSNP: rs762107312
Type: single nucleotide variant
Location: chr10:94592287 (GRCh38)
Gene constraint: LOEUF 0.587 · pLI 0.63 (gnomAD)
Structure: AlphaFold pLDDT 68.76 · 4 PDB
Residue 609: the helicase c-terminal domain

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

Similar variants

HELLS p.Pro609= Likely benign ★ 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-pro609leu (accessed [today's date]).

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