Is HELLS p.Asp693Tyr (c.2077G>T) pathogenic?

HELLS p.Asp693Tyr (c.2077G>T) is classified Uncertain significance in HELLS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-12). AlphaMissense: likely pathogenic (0.9943); Absent from gnomAD v4.1; Associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4.

What condition is associated with HELLS p.Asp693Tyr (c.2077G>T)?

HELLS p.Asp693Tyr (c.2077G>T) is associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4 (ClinVar).

How common is HELLS p.Asp693Tyr (c.2077G>T) in the general population?

HELLS p.Asp693Tyr (c.2077G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HELLS p.Asp693Tyr (c.2077G>T)?

AlphaMissense predicts likely pathogenic (score 0.9943) — an in-silico prediction, not a clinical call.

HELLS p.Asp693Tyr

c.2077G>T · rs1845596397 · VCV998163

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9943 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency-centromeric instability-facial anomalies syndrome 4

Computational evidence

Protein change
AlphaMissense	0.9943	likely pathogenic · top 6% in HELLS
REVEL	0.81	moderately pathogenic-leaning
SaProt	LLR -16.86	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.28	constrained · MANE · 1,268 bp · p 2.1e-10 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HELLS
Protein: p.Asp693Tyr
Coding: c.2077G>T
MANE Select: NM_018063
dbSNP: rs1845596397
Type: single nucleotide variant
Location: chr10:94593604 (GRCh38)
Gene constraint: LOEUF 0.587 · pLI 0.63 (gnomAD)
Structure: AlphaFold pLDDT 68.76 · 4 PDB
Residue 693: the helicase c-terminal 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 p.Asp693= Likely benign ★ same residue
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

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-asp693tyr (accessed [today's date]).

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