Is ARNT p.Phe74Cys (c.221T>G) pathogenic?

ARNT p.Phe74Cys (c.221T>G) is classified Uncertain significance in ARNT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-04). AlphaMissense: likely pathogenic (0.9083); Very rare (popmax 8.48e-05%, nfe).

How common is ARNT p.Phe74Cys (c.221T>G) in the general population?

ARNT p.Phe74Cys (c.221T>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ARNT p.Phe74Cys (c.221T>G)?

AlphaMissense predicts likely pathogenic (score 0.9083) — an in-silico prediction, not a clinical call.

ARNT p.Phe74Cys

c.221T>G · VCV4643099

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9083 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9083	likely pathogenic
REVEL	0.186	benign-leaning
SaProt	LLR -8.49	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 34 kb · p 0.39 · regional, not allelic
Overall
CADD	26.4	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 8.48e-05% European (non-Finnish) · 1/1,179,286 alleles

Overall 6.84e-05% 1/1,460,930 alleles · very rare

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: ARNT
Protein: p.Phe74Cys
Coding: c.221T>G
MANE Select: NM_001668
Type: single nucleotide variant
Location: chr1:150846269 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.53 · 44 PDB
Residue 74: the 'disordered' region

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

Similar variants

ARNT p.Phe74Leu Uncertain significance ★ ⚠ same residue
ARNT p.Asp511Asn Benign/Likely benign ★★ same type
ARNT p.Ala107Gly Uncertain significance ★ ⚠ same type
ARNT p.Ala20Pro Uncertain significance ★ ⚠ same type
ARNT p.Ala687Val Uncertain significance ★ ⚠ same type
ARNT p.Ala84Thr Uncertain significance ★ ⚠ same type
ARNT p.Arg235His Uncertain significance ★ ⚠ same type
ARNT p.Arg43Trp 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/arnt-p-phe74cys (accessed [today's date]).

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