Is HELLS p.Ser419Arg (c.1257T>G) pathogenic?

HELLS p.Ser419Arg (c.1257T>G) is classified Uncertain significance in HELLS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-23). AlphaMissense: ambiguous (0.4365); Very rare (popmax 0.00169%, amr).

How common is HELLS p.Ser419Arg (c.1257T>G) in the general population?

HELLS p.Ser419Arg (c.1257T>G) is very rare (popmax 0.00169%, amr) (gnomAD).

What do computational predictors say about HELLS p.Ser419Arg (c.1257T>G)?

AlphaMissense predicts ambiguous (score 0.4365) — an in-silico prediction, not a clinical call.

HELLS p.Ser419Arg

c.1257T>G · rs144298342 · VCV1493914

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4365 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4365	ambiguous
REVEL	0.687	pathogenic-leaning
SaProt	LLR -8.71	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.48	GERP 0.54, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 6,953 bp · p 2.4e-12 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00169% Admixed American · 1/59,134 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000311% 5/1,605,850 alleles · very rare exomes 5/1,453,560 · genomes 0/152,290 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00169%	59,134
European (non-Finnish)	0.00034%	293,890

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.Ser419Arg
Coding: c.1257T>G
MANE Select: NM_018063
dbSNP: rs144298342
Type: single nucleotide variant
Location: chr10:94582990 (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 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
HELLS p.Arg5Trp 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-ser419arg (accessed [today's date]).

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