Is ARNT p.Ser688Leu (c.2063C>T) pathogenic?

ARNT p.Ser688Leu (c.2063C>T) is classified Uncertain significance in ARNT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-01). AlphaMissense: likely benign (0.1129); Ultra-rare (popmax 0.0128%, nfe).

How common is ARNT p.Ser688Leu (c.2063C>T) in the general population?

ARNT p.Ser688Leu (c.2063C>T) is ultra-rare (popmax 0.0128%, nfe) (gnomAD).

What do computational predictors say about ARNT p.Ser688Leu (c.2063C>T)?

AlphaMissense predicts likely benign (score 0.1129) — an in-silico prediction, not a clinical call.

ARNT p.Ser688Leu

c.2063C>T · rs749440287 · VCV2232941

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1129 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0128%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1129	likely benign
REVEL	0.167	moderately benign-leaning
SaProt	LLR -6.90	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 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 11 kb · p 0.011 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0128% European (non-Finnish) · 151/1,180,056 alleles

Filtering AF 0.0111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0105%

Overall 0.0102% 164/1,614,068 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0128%	7,815
Remaining individualsnot grpmax-eligible	0.008%	12,497
South Asian	0.00549%	18,218
Finnishnot grpmax-eligible	0.00312%	32,016
Admixed American	0.00167%	60,000

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.Ser688Leu
Coding: c.2063C>T
MANE Select: NM_001668
dbSNP: rs749440287
Type: single nucleotide variant
Location: chr1:150814127 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.53 · 44 PDB
Residue 688: the 'disordered' 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.Arg235His Uncertain significance ★ ⚠ same type
ARNT p.Arg43Trp Uncertain significance ★ ⚠ same type
ARNT p.Arg472Gln 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-ser688leu (accessed [today's date]).

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