Is HELLS p.Ala24Pro (c.70G>C) pathogenic?

HELLS p.Ala24Pro (c.70G>C) is classified Uncertain significance in HELLS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-17). AlphaMissense: likely benign (0.0944); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with HELLS p.Ala24Pro (c.70G>C)?

HELLS p.Ala24Pro (c.70G>C) is associated with Inborn genetic diseases (ClinVar).

How common is HELLS p.Ala24Pro (c.70G>C) in the general population?

HELLS p.Ala24Pro (c.70G>C) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about HELLS p.Ala24Pro (c.70G>C)?

AlphaMissense predicts likely benign (score 0.0944) — an in-silico prediction, not a clinical call.

HELLS p.Ala24Pro

c.70G>C · VCV3857388

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0944 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0944	likely benign
REVEL	0.139	moderately benign-leaning
SaProt	LLR -6.17	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	19.24	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 0.004% African / African-American · 3/75,054 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000494%

Overall 0.000248% 4/1,614,164 alleles · very rare exomes 2/1,461,856 · genomes 2/152,308 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	25,018
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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.Ala24Pro
Coding: c.70G>C
MANE Select: NM_018063
Type: single nucleotide variant
Location: chr10:94546415 (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

HELLS p.Ala24= Likely benign ★ same residue
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

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-ala24pro (accessed [today's date]).

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