Is ARID2 p.Phe1680Cys (c.5039T>G) pathogenic?

ARID2 p.Phe1680Cys (c.5039T>G) is classified Uncertain significance in ARID2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-01). AlphaMissense: likely pathogenic (0.983); Very rare (popmax 0.00424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ARID2 p.Phe1680Cys (c.5039T>G)?

ARID2 p.Phe1680Cys (c.5039T>G) is associated with Inborn genetic diseases (ClinVar).

How common is ARID2 p.Phe1680Cys (c.5039T>G) in the general population?

ARID2 p.Phe1680Cys (c.5039T>G) is very rare (popmax 0.00424%, nfe) (gnomAD).

What do computational predictors say about ARID2 p.Phe1680Cys (c.5039T>G)?

AlphaMissense predicts likely pathogenic (score 0.983) — an in-silico prediction, not a clinical call.

ARID2 p.Phe1680Cys

c.5039T>G · VCV3945754

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.983 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00424%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.983	likely pathogenic · top 10% in ARID2
REVEL	0.699	pathogenic-leaning
SaProt	LLR -6.96	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.60 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.32	constrained · MANE · 215 bp · p 1.3e-06 · regional, not allelic
Overall
CADD	27.1	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 0.00424% European (non-Finnish) · 50/1,179,492 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00294%

Overall 0.00383% 56/1,461,280 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,827
European (non-Finnish)grpmax	0.00424%	23,590
South Asian	0.00329%	30,359

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ARID2
Protein: p.Phe1680Cys
Coding: c.5039T>G
MANE Select: NM_152641
Type: single nucleotide variant
Location: chr12:45891896 (GRCh38)
Gene constraint: LOEUF 0.224 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.30 · 2 PDB
Residue 1680: a UniProt-annotated variant site (in css6)

Full ARID2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ARID2 p.Phe1680Leu Uncertain significance ★ ⚠ same residue
ARID2 p.Arg1769Ter Pathogenic ★★ same condition
ARID2 p.Ala1335Glu Uncertain significance ★★ ⚠ same condition
ARID2 p.Asn1280Asp Uncertain significance ★★ ⚠ same condition
ARID2 p.Asp1400Gly Uncertain significance ★★ ⚠ same condition
ARID2 p.Gln752Lys Uncertain significance ★★ ⚠ same condition
ARID2 p.Ile943Phe Uncertain significance ★★ ⚠ same condition
ARID2 p.Ser990Leu Uncertain significance ★★ ⚠ 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/arid2-p-phe1680cys (accessed [today's date]).

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