Is ARNT2 p.Pro334Ser (c.1000C>T) pathogenic?

ARNT2 p.Pro334Ser (c.1000C>T) is classified Uncertain significance in ARNT2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-24). AlphaMissense: ambiguous (0.3653); Rare (popmax 0.165%, mid); Associated with Webb-Dattani syndrome.

What condition is associated with ARNT2 p.Pro334Ser (c.1000C>T)?

ARNT2 p.Pro334Ser (c.1000C>T) is associated with Webb-Dattani syndrome (ClinVar).

How common is ARNT2 p.Pro334Ser (c.1000C>T) in the general population?

ARNT2 p.Pro334Ser (c.1000C>T) is rare (popmax 0.165%, mid) (gnomAD).

What do computational predictors say about ARNT2 p.Pro334Ser (c.1000C>T)?

AlphaMissense predicts ambiguous (score 0.3653) — an in-silico prediction, not a clinical call.

ARNT2 p.Pro334Ser

c.1000C>T · rs145079722 · VCV801401

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3653 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.165%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Webb-Dattani syndrome

Computational evidence

Protein change
AlphaMissense	0.3653	ambiguous
REVEL	0.227	benign-leaning
SaProt	LLR -7.03	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 88 kb · p 0.02 · regional, not allelic
Overall
CADD	24.3	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 0.165% Middle Eastern · 10/6,060 alleles

Filtering AF 0.0895% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0681%

Overall 0.0062% 100/1,614,110 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.165%	606
African / African-American	0.0839%	1,191
Remaining individualsnot grpmax-eligible	0.0112%	8,929
East Asian	0.00223%	44,882
South Asian	0.0022%	45,534
European (non-Finnish)	0.00144%	69,411

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.Pro334Ser
Coding: c.1000C>T
MANE Select: NM_014862
dbSNP: rs145079722
Type: single nucleotide variant
Location: chr15:80552685 (GRCh38)
Gene constraint: LOEUF 0.498 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 59.49
Residue 334: the pas 2 domain

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

Disease context

Webb-Dattani syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ARNT2 p.Arg159Ter Pathogenic/Likely pathogenic ★★ same condition
ARNT2 p.Gly472Ser Uncertain significance ★★ ⚠ same condition
ARNT2 c.1513+29G>C Benign ★★ same condition
ARNT2 c.1513+78T>C Benign ★★ same condition
ARNT2 c.1918+18G>A Benign/Likely benign ★★ same condition
ARNT2 c.195-16C>T Benign/Likely benign ★★ same condition
ARNT2 c.726-69T>C Benign ★★ same condition
ARNT2 p.Gly679Ser Benign ★★ same condition

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-pro334ser (accessed [today's date]).

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