Is ARNT2 p.Val438Ile (c.1312G>A) pathogenic?

ARNT2 p.Val438Ile (c.1312G>A) is classified Conflicting classifications of pathogenicity in ARNT2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-20). AlphaMissense: likely benign (0.1171); Ultra-rare (popmax 0.0446%, eas).

How common is ARNT2 p.Val438Ile (c.1312G>A) in the general population?

ARNT2 p.Val438Ile (c.1312G>A) is ultra-rare (popmax 0.0446%, eas) (gnomAD).

What do computational predictors say about ARNT2 p.Val438Ile (c.1312G>A)?

AlphaMissense predicts likely benign (score 0.1171) — an in-silico prediction, not a clinical call.

ARNT2 p.Val438Ile

c.1312G>A · rs537962071 · VCV2896371

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1171 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1171	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -6.87	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 9.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 30 kb · p 0.066 · regional, not allelic
Overall
CADD	25.7	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 0.0446% East Asian · 20/44,878 alleles

Filtering AF 0.0295% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0246%

Overall 0.00551% 89/1,614,096 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0446%	2,244
Middle Eastern	0.0165%	6,062
Finnishnot grpmax-eligible	0.00781%	12,802
South Asian	0.00769%	13,009
European (non-Finnish)	0.00458%	21,852
Remaining individualsnot grpmax-eligible	0.0032%	31,252

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.Val438Ile
Coding: c.1312G>A
MANE Select: NM_014862
dbSNP: rs537962071
Type: single nucleotide variant
Location: chr15:80563235 (GRCh38)
Gene constraint: LOEUF 0.498 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 59.49
Residue 438: the pac domain

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-val438ile (accessed [today's date]).

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