Is IQSEC2 p.Pro550Ala (c.1648C>G) pathogenic?

IQSEC2 p.Pro550Ala (c.1648C>G) is classified Conflicting classifications of pathogenicity in IQSEC2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-22). AlphaMissense: likely benign (0.0625); Ultra-rare (popmax 0.0567%, amr); Associated with Inborn genetic diseases.

What condition is associated with IQSEC2 p.Pro550Ala (c.1648C>G)?

IQSEC2 p.Pro550Ala (c.1648C>G) is associated with Inborn genetic diseases, intellectual disability, X-linked 1 (ClinVar).

How common is IQSEC2 p.Pro550Ala (c.1648C>G) in the general population?

IQSEC2 p.Pro550Ala (c.1648C>G) is ultra-rare (popmax 0.0567%, amr) (gnomAD).

What do computational predictors say about IQSEC2 p.Pro550Ala (c.1648C>G)?

AlphaMissense predicts likely benign (score 0.0625) — an in-silico prediction, not a clinical call.

IQSEC2 p.Pro550Ala

c.1648C>G · rs782469479 · VCV1277139

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0625 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0567%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0625	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -6.93	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 3.3	GERP 0.96, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 4,397 bp · p 6.5e-09 · regional, not allelic
Overall
CADD	15.23	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 0.0567% Admixed American · 26/45,875 alleles

Filtering AF 0.0397% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.034%

Overall 0.00265% 32/1,208,602 alleles · ultra-rare exomes 21/1,095,781 · genomes 11/112,821 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0567%	1,764
Remaining individualsnot grpmax-eligible	0.00211%	47,471
European (non-Finnish)	0.000559%	178,801

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: IQSEC2
Protein: p.Pro550Ala
Coding: c.1648C>G
MANE Select: NM_001111125
dbSNP: rs782469479
Type: single nucleotide variant
Location: chrX:53250928 (GRCh38)
Structure: AlphaFold pLDDT 54.46 · 2 PDB
Residue 550: 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

Also linked: intellectual disability, X-linked 1

Similar variants

IQSEC2 p.Pro550Leu Uncertain significance ★ ⚠ same residue
IQSEC2 c.2459+21C>T Pathogenic ★★ same condition
IQSEC2 c.2889+1G>A Pathogenic ★★ same condition
IQSEC2 p.Ala836Val Pathogenic/Likely pathogenic ★★ same condition
IQSEC2 p.Arg1055Ter Pathogenic ★★ same condition
IQSEC2 p.Arg1145Ter Pathogenic ★★ same condition
IQSEC2 p.Arg359His Likely pathogenic ★★ same condition
IQSEC2 p.Arg531Ter Pathogenic/Likely pathogenic ★★ 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-pro550ala (accessed [today's date]).

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