Is ARNT2 p.Ser669= (c.2007C>T) pathogenic?

ARNT2 p.Ser669= (c.2007C>T) is classified Benign/Likely benign in ARNT2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-29). Low-frequency (popmax 4.19%, amr); Associated with Webb-Dattani syndrome.

What condition is associated with ARNT2 p.Ser669= (c.2007C>T)?

ARNT2 p.Ser669= (c.2007C>T) is associated with Webb-Dattani syndrome (ClinVar).

How common is ARNT2 p.Ser669= (c.2007C>T) in the general population?

ARNT2 p.Ser669= (c.2007C>T) is low-frequency (popmax 4.19%, amr) (gnomAD).

ARNT2 p.Ser669=

c.2007C>T · rs61753570 · VCV771477

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.19%, amr)

Conditions

Webb-Dattani syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.57 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.51	GERP 0.47, phastCons 1
Overall
CADD	13.44	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.19% Admixed American · 2,514/60,026 alleles

Filtering AF 4.05% ClinGen BA1/BS1 input FAF95, joint · FAF99 4%

Overall 0.222% 3,586/1,614,094 alleles · low-frequency

Ancestry group	Frequency	1 in
Admixed Americangrpmax	4.19%	24
East Asian	1.2%	83
Remaining individualsnot grpmax-eligible	0.325%	308
African / African-American	0.179%	560
Finnishnot grpmax-eligible	0.0984%	1,016
South Asian	0.0242%	4,140
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.00932%	10,727
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604

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.Ser669=
Coding: c.2007C>T
MANE Select: NM_014862
dbSNP: rs61753570
Type: single nucleotide variant
Location: chr15:80591656 (GRCh38)
Gene constraint: LOEUF 0.498 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 59.49
Residue 669: the 'disordered' region

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 p.Pro334Ser 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

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-ser669 (accessed [today's date]).

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