Is HELLS p.Asp831Val (c.2492A>T) pathogenic?

HELLS p.Asp831Val (c.2492A>T) is classified Uncertain significance in HELLS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-09). AlphaMissense: likely benign (0.0853); Ultra-rare (popmax 0.0379%, nfe); Associated with Inborn genetic diseases.

What condition is associated with HELLS p.Asp831Val (c.2492A>T)?

HELLS p.Asp831Val (c.2492A>T) is associated with Inborn genetic diseases (ClinVar).

How common is HELLS p.Asp831Val (c.2492A>T) in the general population?

HELLS p.Asp831Val (c.2492A>T) is ultra-rare (popmax 0.0379%, nfe) (gnomAD).

What do computational predictors say about HELLS p.Asp831Val (c.2492A>T)?

AlphaMissense predicts likely benign (score 0.0853) — an in-silico prediction, not a clinical call.

HELLS p.Asp831Val

c.2492A>T · rs150576597 · VCV1442628

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0853 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0853	likely benign
REVEL	0.585	indeterminate
SaProt	LLR -6.48	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 6.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 6,790 bp · p 0.066 · regional, not allelic
Overall
CADD	23.2	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 0.0379% European (non-Finnish) · 437/1,151,966 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0338%

Overall 0.0297% 469/1,577,162 alleles · ultra-rare exomes 433/1,424,850 · genomes 36/152,312 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0379%	2,636
Remaining individualsnot grpmax-eligible	0.0327%	3,062
Admixed American	0.0174%	5,763
African / African-American	0.0027%	36,975

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.Asp831Val
Coding: c.2492A>T
MANE Select: NM_018063
dbSNP: rs150576597
Type: single nucleotide variant
Location: chr10:94601597 (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

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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-asp831val (accessed [today's date]).

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