Is HELLS p.Ile816Val (c.2446A>G) pathogenic?

HELLS p.Ile816Val (c.2446A>G) is classified Likely benign in HELLS (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-25). AlphaMissense: likely benign (0.0526); Rare (popmax 0.299%, afr).

How common is HELLS p.Ile816Val (c.2446A>G) in the general population?

HELLS p.Ile816Val (c.2446A>G) is rare (popmax 0.299%, afr) (gnomAD).

What do computational predictors say about HELLS p.Ile816Val (c.2446A>G)?

AlphaMissense predicts likely benign (score 0.0526) — an in-silico prediction, not a clinical call.

HELLS p.Ile816Val

c.2446A>G · rs147978849 · VCV791306

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0526 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.299%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0526	likely benign
REVEL	0.23	benign-leaning
SaProt	LLR -5.70	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 0.33	GERP -3.4
Regional constraint	o/e 0.82	unconstrained · MANE · 6,790 bp · p 0.066 · regional, not allelic
Overall
CADD	2.361	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 0.299% African / African-American · 221/73,916 alleles

Filtering AF 0.267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.254%

Overall 0.0159% 249/1,569,434 alleles · rare exomes 102/1,417,152 · genomes 147/152,282 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.299%	334
Admixed American	0.0224%	4,472
Remaining individualsnot grpmax-eligible	0.0213%	4,692
European (non-Finnish)	0.000175%	571,945

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.Ile816Val
Coding: c.2446A>G
MANE Select: NM_018063
dbSNP: rs147978849
Type: single nucleotide variant
Location: chr10:94601551 (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-ile816val (accessed [today's date]).

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