Is HELLS p.Thr305Ala (c.913A>G) pathogenic?

HELLS p.Thr305Ala (c.913A>G) is classified Likely benign in HELLS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0746); Rare (popmax 0.381%, mid); Associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4.

What condition is associated with HELLS p.Thr305Ala (c.913A>G)?

HELLS p.Thr305Ala (c.913A>G) is associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4 (ClinVar).

How common is HELLS p.Thr305Ala (c.913A>G) in the general population?

HELLS p.Thr305Ala (c.913A>G) is rare (popmax 0.381%, mid) (gnomAD).

What do computational predictors say about HELLS p.Thr305Ala (c.913A>G)?

AlphaMissense predicts likely benign (score 0.0746) — an in-silico prediction, not a clinical call.

HELLS p.Thr305Ala

c.913A>G · rs200482346 · VCV739088

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0746 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.381%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency-centromeric instability-facial anomalies syndrome 4

Computational evidence

Protein change
AlphaMissense	0.0746	likely benign
REVEL	0.168	moderately benign-leaning
SaProt	LLR -7.92	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 4.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 6,650 bp · p 0.0061 · regional, not allelic
Overall
CADD	16.04	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 0.381% Middle Eastern · 23/6,044 alleles

Filtering AF 0.286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.274%

Overall 0.0368% 591/1,606,366 alleles · rare exomes 545/1,454,076 · genomes 46/152,290 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.381%	263
South Asian	0.316%	317
Ashkenazi Jewishnot grpmax-eligible	0.197%	509
Remaining individualsnot grpmax-eligible	0.053%	1,886
Admixed American	0.0167%	5,986
European (non-Finnish)	0.0153%	6,556
African / African-American	0.00267%	37,451

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.Thr305Ala
Coding: c.913A>G
MANE Select: NM_018063
dbSNP: rs200482346
Type: single nucleotide variant
Location: chr10:94576686 (GRCh38)
Gene constraint: LOEUF 0.587 · pLI 0.63 (gnomAD)
Structure: AlphaFold pLDDT 68.76 · 4 PDB
Residue 305: the helicase atp-binding domain

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

Disease context

immunodeficiency-centromeric instability-facial anomalies syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HELLS c.370+2T>A Pathogenic ★★ same condition
HELLS p.Arg513Gly Uncertain significance ★★ ⚠ same condition
HELLS p.Leu420Val Uncertain significance ★★ ⚠ same condition
HELLS c.153+10G>T Benign/Likely benign ★★ same condition
HELLS c.31+20T>C Benign ★★ same condition
HELLS c.706-18A>G Likely benign ★★ same condition
HELLS p.Gln90= Benign ★★ same condition
HELLS p.Glu655= Benign ★★ 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-thr305ala (accessed [today's date]).

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