Is ARNT p.Arg235His (c.704G>A) pathogenic?

ARNT p.Arg235His (c.704G>A) is classified Uncertain significance in ARNT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-29). AlphaMissense: likely pathogenic (0.9704); Very rare (popmax 0.00801%, afr).

How common is ARNT p.Arg235His (c.704G>A) in the general population?

ARNT p.Arg235His (c.704G>A) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about ARNT p.Arg235His (c.704G>A)?

AlphaMissense predicts likely pathogenic (score 0.9704) — an in-silico prediction, not a clinical call.

ARNT p.Arg235His

c.704G>A · VCV3315881

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9704 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9704	likely pathogenic
REVEL	0.444	indeterminate
SaProt	LLR -12.76	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 5.9	GERP 2, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 19 kb · p 3.2e-13 · regional, not allelic
Overall
CADD	28.7	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 0.00801% African / African-American · 6/74,886 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.00143% 23/1,613,344 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,481
Finnishnot grpmax-eligible	0.00313%	31,973
Admixed American	0.00167%	59,970
Remaining individualsnot grpmax-eligible	0.0016%	62,438
European (non-Finnish)	0.0011%	90,739

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: ARNT
Protein: p.Arg235His
Coding: c.704G>A
MANE Select: NM_001668
Type: single nucleotide variant
Location: chr1:150834637 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.53 · 44 PDB
Residue 235: the pas 1 domain; the 'required for heterodimer formation with epas1' region

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

Similar variants

ARNT p.Asp511Asn Benign/Likely benign ★★ same type
ARNT p.Ala107Gly Uncertain significance ★ ⚠ same type
ARNT p.Ala20Pro Uncertain significance ★ ⚠ same type
ARNT p.Ala687Val Uncertain significance ★ ⚠ same type
ARNT p.Ala84Thr Uncertain significance ★ ⚠ same type
ARNT p.Arg43Trp Uncertain significance ★ ⚠ same type
ARNT p.Arg472Gln Uncertain significance ★ ⚠ same type
ARNT p.Arg481Lys 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/arnt-p-arg235his (accessed [today's date]).

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