Is ARNT2 p.Ala95Ser (c.283G>T) pathogenic?

ARNT2 p.Ala95Ser (c.283G>T) is classified Uncertain significance in ARNT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-23). AlphaMissense: ambiguous (0.3907); Very rare (popmax 8.47e-05%, nfe).

How common is ARNT2 p.Ala95Ser (c.283G>T) in the general population?

ARNT2 p.Ala95Ser (c.283G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ARNT2 p.Ala95Ser (c.283G>T)?

AlphaMissense predicts ambiguous (score 0.3907) — an in-silico prediction, not a clinical call.

ARNT2 p.Ala95Ser

c.283G>T · rs1377714549 · VCV2116830

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3907 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3907	ambiguous
REVEL	0.673	pathogenic-leaning
SaProt	LLR -10.82	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 17 kb · p 5.5e-08 · regional, not allelic
Overall
CADD	24.6	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 8.47e-05% European (non-Finnish) · 1/1,180,020 alleles

Overall 6.84e-05% 1/1,461,886 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: ARNT2
Protein: p.Ala95Ser
Coding: c.283G>T
MANE Select: NM_014862
dbSNP: rs1377714549
Type: single nucleotide variant
Location: chr15:80470306 (GRCh38)
Gene constraint: LOEUF 0.498 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 59.49
Residue 95: the bhlh domain

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

Similar variants

ARNT2 p.Ala95Thr 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
ARNT2 p.Gly546Arg 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-ala95ser (accessed [today's date]).

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