Is ARNT2 p.Ser166Cys (c.497C>G) pathogenic?

ARNT2 p.Ser166Cys (c.497C>G) is classified Uncertain significance in ARNT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-07). AlphaMissense: likely pathogenic (0.9707); Very rare (popmax 0.0011%, sas).

How common is ARNT2 p.Ser166Cys (c.497C>G) in the general population?

ARNT2 p.Ser166Cys (c.497C>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ARNT2 p.Ser166Cys (c.497C>G)?

AlphaMissense predicts likely pathogenic (score 0.9707) — an in-silico prediction, not a clinical call.

ARNT2 p.Ser166Cys

c.497C>G · rs1327764647 · VCV1504053

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9707 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9707	likely pathogenic
REVEL	0.514	indeterminate
SaProt	LLR -13.80	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 88 kb · p 0.02 · regional, not allelic
Overall
CADD	25.8	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

Grpmax group 0.0011% South Asian · 1/91,086 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000805% 13/1,614,070 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,086
European (non-Finnish)	0.00102%	98,338

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: ARNT2
Protein: p.Ser166Cys
Coding: c.497C>G
MANE Select: NM_014862
dbSNP: rs1327764647
Type: single nucleotide variant
Location: chr15:80475098 (GRCh38)
Gene constraint: LOEUF 0.498 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 59.49
Residue 166: the pas 1 domain

Full ARNT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARNT2 p.Arg159Ter Pathogenic/Likely pathogenic ★★ same type
ARNT2 p.Ala483Val Uncertain significance ★★ ⚠ same type
ARNT2 p.Arg262Lys Uncertain significance ★★ ⚠ same type
ARNT2 p.Asp705Tyr Uncertain significance ★★ ⚠ same type
ARNT2 p.Gln520Arg Uncertain significance ★★ ⚠ same type
ARNT2 p.Gly472Ser Uncertain significance ★★ ⚠ same type
ARNT2 p.Gly546Arg Uncertain significance ★★ ⚠ same type
ARNT2 p.Ile347Phe 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/arnt2-p-ser166cys (accessed [today's date]).

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