Is IQSEC2 p.Pro642Arg (c.1925C>G) pathogenic?

IQSEC2 p.Pro642Arg (c.1925C>G) is classified Uncertain significance in IQSEC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-09-26). AlphaMissense: ambiguous (0.3796); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with IQSEC2 p.Pro642Arg (c.1925C>G)?

IQSEC2 p.Pro642Arg (c.1925C>G) is associated with Inborn genetic diseases (ClinVar).

How common is IQSEC2 p.Pro642Arg (c.1925C>G) in the general population?

IQSEC2 p.Pro642Arg (c.1925C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IQSEC2 p.Pro642Arg (c.1925C>G)?

AlphaMissense predicts ambiguous (score 0.3796) — an in-silico prediction, not a clinical call.

IQSEC2 p.Pro642Arg

c.1925C>G · rs2074371712 · VCV1782754

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3796 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3796	ambiguous
REVEL	0.146	moderately benign-leaning
SaProt	LLR -7.16	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 4,397 bp · p 6.5e-09 · regional, not allelic
Overall
CADD	25.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: IQSEC2
Protein: p.Pro642Arg
Coding: c.1925C>G
MANE Select: NM_001111125
dbSNP: rs2074371712
Type: single nucleotide variant
Location: chrX:53250651 (GRCh38)
Structure: AlphaFold pLDDT 54.46 · 2 PDB
Residue 642: the 'disordered' region

Full IQSEC2 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

IQSEC2 p.Pro642= Conflicting classifications of pathogenicity ★ same residue
IQSEC2 p.Pro642Leu Uncertain significance ★★ ⚠ same residue
IQSEC2 p.Arg359His Likely pathogenic ★★ same condition
IQSEC2 p.Arg531Ter Pathogenic/Likely pathogenic ★★ same condition
IQSEC2 p.Arg758Ter Pathogenic ★★ same condition
IQSEC2 c.2582+3G>T Uncertain significance ★★ same condition
IQSEC2 c.708-3C>T Uncertain significance ★★ same condition
IQSEC2 p.Arg1090His 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/iqsec2-p-pro642arg (accessed [today's date]).

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