Is INTS1 p.Arg1344Gln (c.4031G>A) pathogenic?

INTS1 p.Arg1344Gln (c.4031G>A) is classified Uncertain significance in INTS1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-07-25). AlphaMissense: likely benign (0.0795); Rare (popmax 0.283%, afr).

How common is INTS1 p.Arg1344Gln (c.4031G>A) in the general population?

INTS1 p.Arg1344Gln (c.4031G>A) is rare (popmax 0.283%, afr) (gnomAD).

What do computational predictors say about INTS1 p.Arg1344Gln (c.4031G>A)?

AlphaMissense predicts likely benign (score 0.0795) — an in-silico prediction, not a clinical call.

INTS1 p.Arg1344Gln

c.4031G>A · VCV3906601

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0795 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.283%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0795	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -6.77	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 1.3	GERP -1.8, phastCons 0.75
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	20.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.283% African / African-American · 212/75,018 alleles

Filtering AF 0.251% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.239%

Overall 0.0295% 475/1,611,710 alleles · rare exomes 354/1,459,364 · genomes 121/152,346 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.283%	354
Remaining individualsnot grpmax-eligible	0.0337%	2,970
European (non-Finnish)	0.0197%	5,084
Middle Eastern	0.0189%	5,290
Admixed American	0.00835%	11,980
South Asian	0.0044%	22,725

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: INTS1
Protein: p.Arg1344Gln
Coding: c.4031G>A
MANE Select: NM_001080453
Type: single nucleotide variant
Location: chr7:1480360 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB

Full INTS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

INTS1 p.Arg1344Trp Uncertain significance ★ ⚠ same residue
INTS1 c.3430-2A>C Likely pathogenic ★★ same type
INTS1 p.Arg101Ter Likely pathogenic ★★ same type
INTS1 p.Glu182Ter Likely pathogenic ★★ same type
INTS1 c.1283+5G>A Uncertain significance ★★ same type
INTS1 c.2977-5C>T Uncertain significance ★★ same type
INTS1 p.Ala1112Val Uncertain significance ★★ ⚠ same type
INTS1 p.Ala1505Val 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/ints1-p-arg1344gln (accessed [today's date]).

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