Is HELLS p.Met1Thr (c.2T>C) pathogenic?

HELLS p.Met1Thr (c.2T>C) is classified Conflicting classifications of pathogenicity in HELLS (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-01). Low-frequency (popmax 1.64%, afr); Associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4.

What condition is associated with HELLS p.Met1Thr (c.2T>C)?

HELLS p.Met1Thr (c.2T>C) is associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4 (ClinVar).

How common is HELLS p.Met1Thr (c.2T>C) in the general population?

HELLS p.Met1Thr (c.2T>C) is low-frequency (popmax 1.64%, afr) (gnomAD).

HELLS p.Met1Thr

c.2T>C · rs113154675 · VCV716400

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

low-frequency (popmax 1.64%, afr)

Conditions

immunodeficiency-centromeric instability-facial anomalies syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.525	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 0.61, phastCons 1
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.64% African / African-American · 1,208/73,500 alleles

Filtering AF 1.57% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.54%

Overall 0.0998% 1,552/1,555,604 alleles · low-frequency exomes 871/1,403,286 · genomes 681/152,318 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.64%	61
Middle Eastern	0.3%	333
Remaining individualsnot grpmax-eligible	0.174%	574
Admixed American	0.152%	658
European (non-Finnish)	0.0117%	8,511
South Asian	0.0083%	12,053
Ashkenazi Jewishnot grpmax-eligible	0.00349%	28,656

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.Met1Thr
Coding: c.2T>C
MANE Select: NM_018063
dbSNP: rs113154675
Type: single nucleotide variant
Location: chr10:94545923 (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

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

Similar variants

HELLS p.Met1Leu Uncertain significance ★ 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-met1thr (accessed [today's date]).

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