Is HELLS p.Ala16Pro (c.46G>C) pathogenic?

HELLS p.Ala16Pro (c.46G>C) is classified Uncertain significance in HELLS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-22). AlphaMissense: likely benign (0.0856); Very rare (popmax 0.00568%, nfe); Associated with Inborn genetic diseases.

What condition is associated with HELLS p.Ala16Pro (c.46G>C)?

HELLS p.Ala16Pro (c.46G>C) is associated with Inborn genetic diseases (ClinVar).

How common is HELLS p.Ala16Pro (c.46G>C) in the general population?

HELLS p.Ala16Pro (c.46G>C) is very rare (popmax 0.00568%, nfe) (gnomAD).

What do computational predictors say about HELLS p.Ala16Pro (c.46G>C)?

AlphaMissense predicts likely benign (score 0.0856) — an in-silico prediction, not a clinical call.

HELLS p.Ala16Pro

c.46G>C · rs773580902 · VCV1373113

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0856 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00568%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0856	likely benign
REVEL	0.245	benign-leaning
SaProt	LLR -6.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 1.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,258 bp · p 0.71 · regional, not allelic
Overall
CADD	16.92	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 0.00568% European (non-Finnish) · 67/1,180,054 alleles

Filtering AF 0.00453% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00417%

Overall 0.00427% 69/1,614,066 alleles · very rare exomes 63/1,461,864 · genomes 6/152,202 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00568%	17,613
Admixed American	0.00167%	60,006
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Ala16Pro
Coding: c.46G>C
MANE Select: NM_018063
dbSNP: rs773580902
Type: single nucleotide variant
Location: chr10:94546391 (GRCh38)
Gene constraint: LOEUF 0.587 · pLI 0.63 (gnomAD)
Structure: AlphaFold pLDDT 68.76 · 4 PDB

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

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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
HELLS p.Asp523Val 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-ala16pro (accessed [today's date]).

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