Is ARNT p.Ser180Leu (c.539C>T) pathogenic?

ARNT p.Ser180Leu (c.539C>T) is classified Uncertain significance in ARNT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: ambiguous (0.4745); Ultra-rare (popmax 0.0472%, sas).

How common is ARNT p.Ser180Leu (c.539C>T) in the general population?

ARNT p.Ser180Leu (c.539C>T) is ultra-rare (popmax 0.0472%, sas) (gnomAD).

What do computational predictors say about ARNT p.Ser180Leu (c.539C>T)?

AlphaMissense predicts ambiguous (score 0.4745) — an in-silico prediction, not a clinical call.

ARNT p.Ser180Leu

c.539C>T · VCV4147664

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4745 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0472%, sas)

Computational evidence

Protein change
AlphaMissense	0.4745	ambiguous
REVEL	0.608	indeterminate
SaProt	LLR -10.70	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 19 kb · p 3.2e-13 · regional, not allelic
Overall
CADD	29.4	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 0.0472% South Asian · 43/91,088 alleles

Filtering AF 0.036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0321%

Overall 0.00781% 126/1,614,004 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0472%	2,118
European (non-Finnish)	0.00669%	14,937
Remaining individualsnot grpmax-eligible	0.0032%	31,242
Finnishnot grpmax-eligible	0.00312%	32,004

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.Ser180Leu
Coding: c.539C>T
MANE Select: NM_001668
Type: single nucleotide variant
Location: chr1:150836441 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.53 · 44 PDB
Residue 180: the pas 1 domain; a β-strand; the 'required for heterodimer formation with epas1' region

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

Similar variants

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
ARNT p.Arg472Gln 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-ser180leu (accessed [today's date]).

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