Is HELLS p.Thr625Ala (c.1873A>G) pathogenic?

HELLS p.Thr625Ala (c.1873A>G) is classified Uncertain significance in HELLS (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-24). AlphaMissense: likely benign (0.3027); Very rare (popmax 0.000513%, nfe).

How common is HELLS p.Thr625Ala (c.1873A>G) in the general population?

HELLS p.Thr625Ala (c.1873A>G) is very rare (popmax 0.000513%, nfe) (gnomAD).

What do computational predictors say about HELLS p.Thr625Ala (c.1873A>G)?

AlphaMissense predicts likely benign (score 0.3027) — an in-silico prediction, not a clinical call.

HELLS p.Thr625Ala

c.1873A>G · rs967920934 · VCV1472781

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3027 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000513%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3027	likely benign
REVEL	0.694	pathogenic-leaning
SaProt	LLR -10.45	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 5,267 bp · p 2e-05 · regional, not allelic
Overall
CADD	26.6	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 0.000513% European (non-Finnish) · 6/1,168,926 alleles

Filtering AF 0.000185% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000379% 6/1,582,964 alleles · very rare exomes 6/1,430,640 · genomes 0/152,324 · joint denominator

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.Thr625Ala
Coding: c.1873A>G
MANE Select: NM_018063
dbSNP: rs967920934
Type: single nucleotide variant
Location: chr10:94592416 (GRCh38)
Gene constraint: LOEUF 0.587 · pLI 0.63 (gnomAD)
Structure: AlphaFold pLDDT 68.76 · 4 PDB
Residue 625: the helicase c-terminal domain

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

Similar variants

HELLS p.Thr625Ile Uncertain significance ★ ⚠ 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-thr625ala (accessed [today's date]).

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