Is HELLS p.Tyr347Cys (c.1040A>G) pathogenic?

HELLS p.Tyr347Cys (c.1040A>G) is classified Uncertain significance in HELLS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-15). AlphaMissense: likely benign (0.0818); Very rare (popmax 0.00218%, amr); Associated with Inborn genetic diseases.

What condition is associated with HELLS p.Tyr347Cys (c.1040A>G)?

HELLS p.Tyr347Cys (c.1040A>G) is associated with Inborn genetic diseases (ClinVar).

How common is HELLS p.Tyr347Cys (c.1040A>G) in the general population?

HELLS p.Tyr347Cys (c.1040A>G) is very rare (popmax 0.00218%, amr) (gnomAD).

What do computational predictors say about HELLS p.Tyr347Cys (c.1040A>G)?

AlphaMissense predicts likely benign (score 0.0818) — an in-silico prediction, not a clinical call.

HELLS p.Tyr347Cys

c.1040A>G · rs377515394 · VCV3105071

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0818 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00218%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0818	likely benign
REVEL	0.63	indeterminate
SaProt	LLR -7.25	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.67, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 6,650 bp · p 0.0061 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00218% Admixed American · 1/45,824 alleles

Filtering AF 0.00142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0012%

Overall 0.00169% 26/1,537,256 alleles · very rare exomes 19/1,385,090 · genomes 7/152,166 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00218%	45,824
European (non-Finnish)	0.0021%	47,556
African / African-American	0.00139%	72,126

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.Tyr347Cys
Coding: c.1040A>G
MANE Select: NM_018063
dbSNP: rs377515394
Type: single nucleotide variant
Location: chr10:94581333 (GRCh38)
Gene constraint: LOEUF 0.587 · pLI 0.63 (gnomAD)
Structure: AlphaFold pLDDT 68.76 · 4 PDB
Residue 347: the helicase atp-binding domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HELLS p.Ala16Pro Uncertain significance ★★ ⚠ same condition
HELLS p.Arg319Trp Uncertain significance ★★ ⚠ same condition
HELLS p.Arg507Gln Uncertain significance ★★ ⚠ same condition
HELLS p.Arg541Gln Uncertain significance ★★ ⚠ same condition
HELLS p.Arg5Trp Uncertain significance ★★ ⚠ same condition
HELLS p.Arg66Cys Uncertain significance ★★ ⚠ same condition
HELLS p.Arg721Cys Uncertain significance ★★ ⚠ same condition
HELLS p.Asp117Gly Uncertain significance ★★ ⚠ 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-tyr347cys (accessed [today's date]).

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