Is HELLS p.Val313Leu (c.937G>C) pathogenic?

HELLS p.Val313Leu (c.937G>C) is classified Uncertain significance in HELLS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-27). AlphaMissense: likely benign (0.0951); Very rare (popmax 0.00334%, amr).

How common is HELLS p.Val313Leu (c.937G>C) in the general population?

HELLS p.Val313Leu (c.937G>C) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about HELLS p.Val313Leu (c.937G>C)?

AlphaMissense predicts likely benign (score 0.0951) — an in-silico prediction, not a clinical call.

HELLS p.Val313Leu

c.937G>C · rs754419257 · VCV1355822

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0951 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0951	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -5.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.57	donor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.4	GERP 1.2, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 6,650 bp · p 0.0061 · regional, not allelic
Overall
CADD	22.1	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 0.00334% Admixed American · 2/59,924 alleles

Filtering AF 0.000554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000248% 4/1,610,474 alleles · very rare exomes 4/1,458,276 · genomes 0/152,198 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,962
European (non-Finnish)	0.00017%	588,588

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.Val313Leu
Coding: c.937G>C
MANE Select: NM_018063
dbSNP: rs754419257
Type: single nucleotide variant
Location: chr10:94576710 (GRCh38)
Gene constraint: LOEUF 0.587 · pLI 0.63 (gnomAD)
Structure: AlphaFold pLDDT 68.76 · 4 PDB
Residue 313: the helicase atp-binding domain

Full HELLS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HELLS p.Val313= Likely benign ★ same residue
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

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-val313leu (accessed [today's date]).

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