Is HELLS p.Pro525= (c.1575T>A) pathogenic?

HELLS p.Pro525= (c.1575T>A) is classified Likely benign in HELLS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-01). Ultra-rare (popmax 0.016%, afr).

How common is HELLS p.Pro525= (c.1575T>A) in the general population?

HELLS p.Pro525= (c.1575T>A) is ultra-rare (popmax 0.016%, afr) (gnomAD).

HELLS p.Pro525=

c.1575T>A · rs940081177 · VCV1625448

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

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 0.89	GERP -1.1, phastCons 1
Overall
CADD	8.939	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.016% African / African-American · 12/74,846 alleles

Filtering AF 0.00922% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.000807% 13/1,611,766 alleles · ultra-rare exomes 5/1,459,540 · genomes 8/152,226 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,237
Remaining individualsnot grpmax-eligible	0.0016%	62,410

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.Pro525=
Coding: c.1575T>A
MANE Select: NM_018063
dbSNP: rs940081177
Type: single nucleotide variant
Location: chr10:94590499 (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

Similar variants

HELLS p.Pro525Arg Uncertain significance ★ ⚠ 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-pro525 (accessed [today's date]).

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