Is HELLS p.Ser60Leu (c.179C>T) pathogenic?

HELLS p.Ser60Leu (c.179C>T) is classified Uncertain significance in HELLS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-15). AlphaMissense: likely benign (0.1293); Very rare (popmax 0.00782%, amr); Associated with Inborn genetic diseases.

What condition is associated with HELLS p.Ser60Leu (c.179C>T)?

HELLS p.Ser60Leu (c.179C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HELLS p.Ser60Leu (c.179C>T) in the general population?

HELLS p.Ser60Leu (c.179C>T) is very rare (popmax 0.00782%, amr) (gnomAD).

What do computational predictors say about HELLS p.Ser60Leu (c.179C>T)?

AlphaMissense predicts likely benign (score 0.1293) — an in-silico prediction, not a clinical call.

HELLS p.Ser60Leu

c.179C>T · rs145174432 · VCV1407456

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1293 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00782%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1293	likely benign
REVEL	0.342	indeterminate
SaProt	LLR -6.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,258 bp · p 0.71 · regional, not allelic
Overall
CADD	25.5	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 0.00782% Admixed American · 4/51,138 alleles

Filtering AF 0.00398% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00364%

Overall 0.00444% 70/1,576,424 alleles · very rare exomes 61/1,424,782 · genomes 9/151,642 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00782%	12,785
European (non-Finnish)	0.00505%	19,790
South Asian	0.00365%	27,411
Remaining individualsnot grpmax-eligible	0.00327%	30,558
African / African-American	0.00275%	36,313

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.Ser60Leu
Coding: c.179C>T
MANE Select: NM_018063
dbSNP: rs145174432
Type: single nucleotide variant
Location: chr10:94554151 (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.Ser60= 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-ser60leu (accessed [today's date]).

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