Is INTS2 p.Gln583= (c.1749A>G) pathogenic?

INTS2 p.Gln583= (c.1749A>G) is classified Benign in INTS2 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2019-10-30). Common (popmax 28.2%, sas) — too common for a highly-penetrant pathogenic allele; Associated with INTS2-related disorder.

What condition is associated with INTS2 p.Gln583= (c.1749A>G)?

INTS2 p.Gln583= (c.1749A>G) is associated with INTS2-related disorder (ClinVar).

INTS2 p.Gln583=

Q: How common is INTS2 p.Gln583= (c.1749A>G) in the general population?

INTS2 p.Gln583= (c.1749A>G) is common (popmax 28.2%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1749A>G · rs753765 · VCV3059600

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 28.2%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

INTS2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -8.2	GERP -4.1
Overall
CADD	0.917	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 28.2% South Asian · 25,674/90,990 alleles

Filtering AF 27.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 27.8%

Overall 7.79% 125,688/1,612,594 alleles · common exomes 115,616/1,460,450 · genomes 10,072/152,144 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	28.2%	4
East Asian	22.7%	4
Amishnot grpmax-eligible	17%	6
Finnishnot grpmax-eligible	8.82%	11
Ashkenazi Jewishnot grpmax-eligible	8.49%	12
Remaining individualsnot grpmax-eligible	7.97%	13
Middle Eastern	7.91%	13
Admixed American	6.77%	15
European (non-Finnish)	6.01%	17
African / African-American	1.66%	60

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: INTS2
Protein: p.Gln583=
Coding: c.1749A>G
MANE Select: NM_001351695
dbSNP: rs753765
Type: single nucleotide variant
Location: chr17:61891639 (GRCh38)
Gene constraint: LOEUF 0.491 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 78.90 · 8 PDB

Full INTS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

INTS2-related disorder

Similar variants

INTS2 c.432+5A>G Likely benign same condition
INTS2 p.Val352Ala Likely benign same condition
INTS2 c.-17A>G Uncertain significance ★ ⚠ same type
INTS2 c.-1A>G Uncertain significance ★ ⚠ same type
INTS2 c.-3A>G Uncertain significance ★ ⚠ same type
INTS2 p.Ala1125Ser Uncertain significance ★ ⚠ same type
INTS2 p.Ala379Val Uncertain significance ★ same type
INTS2 p.Ala400Asp 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/ints2-p-gln583 (accessed [today's date]).

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