Is ARNT2 p.Val312Met (c.934G>A) pathogenic?

ARNT2 p.Val312Met (c.934G>A) is classified Uncertain significance in ARNT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-24). AlphaMissense: likely pathogenic (0.9925); Very rare (popmax 0.00445%, eas).

How common is ARNT2 p.Val312Met (c.934G>A) in the general population?

ARNT2 p.Val312Met (c.934G>A) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about ARNT2 p.Val312Met (c.934G>A)?

AlphaMissense predicts likely pathogenic (score 0.9925) — an in-silico prediction, not a clinical call.

ARNT2 p.Val312Met

c.934G>A · VCV3948443

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9925 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9925	likely pathogenic
REVEL	0.42	indeterminate
SaProt	LLR -13.82	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 11	GERP 1.2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 88 kb · p 0.02 · regional, not allelic
Overall
CADD	27.9	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 0.00445% East Asian · 2/44,898 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000496% 8/1,613,772 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,449
Remaining individualsnot grpmax-eligible	0.0016%	62,478
South Asian	0.0011%	91,076
European (non-Finnish)	0.000339%	294,959

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.Val312Met
Coding: c.934G>A
MANE Select: NM_014862
Type: single nucleotide variant
Location: chr15:80551255 (GRCh38)
Gene constraint: LOEUF 0.498 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 59.49

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-val312met (accessed [today's date]).

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