Is HELLS p.Leu420Val (c.1258C>G) pathogenic?

HELLS p.Leu420Val (c.1258C>G) is classified Uncertain significance in HELLS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-10-30). AlphaMissense: likely benign (0.0888); Rare (popmax 0.149%, nfe); Associated with Inborn genetic diseases.

What condition is associated with HELLS p.Leu420Val (c.1258C>G)?

HELLS p.Leu420Val (c.1258C>G) is associated with Inborn genetic diseases, immunodeficiency-centromeric instability-facial anomalies syndrome 4 (ClinVar).

How common is HELLS p.Leu420Val (c.1258C>G) in the general population?

HELLS p.Leu420Val (c.1258C>G) is rare (popmax 0.149%, nfe) (gnomAD).

What do computational predictors say about HELLS p.Leu420Val (c.1258C>G)?

AlphaMissense predicts likely benign (score 0.0888) — an in-silico prediction, not a clinical call.

HELLS p.Leu420Val

c.1258C>G · rs146569050 · VCV811038

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0888 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.149%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0888	likely benign
REVEL	0.209	benign-leaning
SaProt	LLR -6.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4	GERP 0.95, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 6,953 bp · p 2.4e-12 · regional, not allelic
Overall
CADD	19.36	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 0.149% European (non-Finnish) · 1,756/1,175,222 alleles

Filtering AF 0.144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.141%

Overall 0.12% 1,923/1,605,172 alleles · rare exomes 1,819/1,452,928 · genomes 104/152,244 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.149%	669
Admixed American	0.13%	767
Remaining individualsnot grpmax-eligible	0.105%	957
African / African-American	0.0254%	3,931
Middle Eastern	0.0166%	6,024
South Asian	0.00558%	17,912

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.Leu420Val
Coding: c.1258C>G
MANE Select: NM_018063
dbSNP: rs146569050
Type: single nucleotide variant
Location: chr10:94582991 (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

Also linked: immunodeficiency-centromeric instability-facial anomalies syndrome 4

Similar variants

HELLS c.370+2T>A Pathogenic ★★ same condition
HELLS p.Ala16Pro Uncertain significance ★★ ⚠ same condition
HELLS p.Arg319Trp Uncertain significance ★★ ⚠ same condition
HELLS p.Arg507Gln Uncertain significance ★★ ⚠ same condition
HELLS p.Arg513Gly 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

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-leu420val (accessed [today's date]).

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