Is HELLS p.Ile77= (c.231A>C) pathogenic?

HELLS p.Ile77= (c.231A>C) is classified Benign in HELLS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 68.7%, eas) — too common for a highly-penetrant pathogenic allele; Associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4.

What condition is associated with HELLS p.Ile77= (c.231A>C)?

HELLS p.Ile77= (c.231A>C) is associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4 (ClinVar).

HELLS p.Ile77=

Q: How common is HELLS p.Ile77= (c.231A>C) in the general population?

HELLS p.Ile77= (c.231A>C) is common (popmax 68.7%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.231A>C · rs11188019 · VCV1168418

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 68.7%, eas) — too common for a highly-penetrant pathogenic allele

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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -0.92, phastCons 1
Overall
CADD	8.782	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 68.7% East Asian · 29,835/43,450 alleles

Filtering AF 68% ClinGen BA1/BS1 input FAF95, joint · FAF99 67.7%

Overall 45.2% 712,391/1,576,520 alleles · common exomes 643,713/1,424,594 · genomes 68,678/151,926 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	68.7%	1
South Asian	59.2%	2
African / African-American	48.2%	2
Remaining individualsnot grpmax-eligible	45.9%	2
European (non-Finnish)	44.1%	2
Amishnot grpmax-eligible	43.7%	2
Ashkenazi Jewishnot grpmax-eligible	41.9%	2
Middle Eastern	40.7%	2
Finnishnot grpmax-eligible	36.7%	3
Admixed American	36%	3

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.Ile77=
Coding: c.231A>C
MANE Select: NM_018063
dbSNP: rs11188019
Type: single nucleotide variant
Location: chr10:94554203 (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.Ile77Met Uncertain significance ★ same residue
HELLS p.Ile77Thr 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

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-ile77 (accessed [today's date]).

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