Is IQSEC2 p.Ala259= (c.777G>A) pathogenic?

IQSEC2 p.Ala259= (c.777G>A) is classified Likely benign in IQSEC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-22). Very rare (popmax 0.00176%, afr); Associated with Inborn genetic diseases.

What condition is associated with IQSEC2 p.Ala259= (c.777G>A)?

IQSEC2 p.Ala259= (c.777G>A) is associated with Inborn genetic diseases, intellectual disability, X-linked 1 (ClinVar).

How common is IQSEC2 p.Ala259= (c.777G>A) in the general population?

IQSEC2 p.Ala259= (c.777G>A) is very rare (popmax 0.00176%, afr) (gnomAD).

IQSEC2 p.Ala259=

c.777G>A · rs923484172 · VCV589320

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00176%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.81	GERP -3.6, phastCons 0.005
Overall
CADD	7.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00176% African / African-American · 1/56,704 alleles

Filtering AF 0.00102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000811%

Overall 0.00144% 17/1,183,353 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00215%	46,404
African / African-Americangrpmax	0.00176%	56,704
European (non-Finnish)	0.0017%	58,723

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: IQSEC2
Protein: p.Ala259=
Coding: c.777G>A
MANE Select: NM_001111125
dbSNP: rs923484172
Type: single nucleotide variant
Location: chrX:53256022 (GRCh38)
Structure: AlphaFold pLDDT 54.46 · 2 PDB
Residue 259: 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.Ala259Thr Uncertain significance ★ ⚠ same residue
IQSEC2 p.Ala259Val Likely benign ★ 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

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-ala259 (accessed [today's date]).

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