Is ARNT2 p.Pro691Ser (c.2071C>T) pathogenic?

ARNT2 p.Pro691Ser (c.2071C>T) is classified Uncertain significance in ARNT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely benign (0.0665); Very rare (popmax 0.00134%, afr).

How common is ARNT2 p.Pro691Ser (c.2071C>T) in the general population?

ARNT2 p.Pro691Ser (c.2071C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about ARNT2 p.Pro691Ser (c.2071C>T)?

AlphaMissense predicts likely benign (score 0.0665) — an in-silico prediction, not a clinical call.

ARNT2 p.Pro691Ser

c.2071C>T · VCV4147821

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0665 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0665	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -5.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 0.73, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 30 kb · p 0.066 · regional, not allelic
Overall
CADD	19.64	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00134% African / African-American · 1/74,904 alleles

Overall 6.25e-05% 1/1,600,598 alleles · very rare exomes 1/1,448,274 · genomes 0/152,324 · joint denominator

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.Pro691Ser
Coding: c.2071C>T
MANE Select: NM_014862
Type: single nucleotide variant
Location: chr15:80593615 (GRCh38)
Gene constraint: LOEUF 0.498 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 59.49
Residue 691: the 'disordered' region

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-pro691ser (accessed [today's date]).

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