Is ARNT2 p.Arg42Pro (c.125G>C) pathogenic?

ARNT2 p.Arg42Pro (c.125G>C) is classified Uncertain significance in ARNT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-13). AlphaMissense: likely pathogenic (0.6258); Ultra-rare (popmax 0.0149%, nfe).

How common is ARNT2 p.Arg42Pro (c.125G>C) in the general population?

ARNT2 p.Arg42Pro (c.125G>C) is ultra-rare (popmax 0.0149%, nfe) (gnomAD).

What do computational predictors say about ARNT2 p.Arg42Pro (c.125G>C)?

AlphaMissense predicts likely pathogenic (score 0.6258) — an in-silico prediction, not a clinical call.

ARNT2 p.Arg42Pro

c.125G>C · rs750470628 · VCV2454686

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6258 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0149%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6258	likely pathogenic
REVEL	0.273	benign-leaning
SaProt	LLR -6.64	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 8.3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 53 kb · p 0.6 · regional, not allelic
Overall
CADD	26.9	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 0.0149% European (non-Finnish) · 176/1,179,988 alleles

Filtering AF 0.0131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.0115% 185/1,613,836 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0149%	6,704
Remaining individualsnot grpmax-eligible	0.0096%	10,414
African / African-American	0.00267%	37,469
Admixed American	0.00167%	59,994

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.Arg42Pro
Coding: c.125G>C
MANE Select: NM_014862
dbSNP: rs750470628
Type: single nucleotide variant
Location: chr15:80450973 (GRCh38)
Gene constraint: LOEUF 0.498 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 59.49
Residue 42: a modified residue (omega-n-methylarginine); the 'disordered' region

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

Similar variants

ARNT2 p.Arg42Cys Uncertain significance ★ ⚠ same residue
ARNT2 p.Arg42His Uncertain significance ★ ⚠ same residue
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

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-arg42pro (accessed [today's date]).

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