Is INTS1 p.Arg1867Trp (c.5599C>T) pathogenic?

INTS1 p.Arg1867Trp (c.5599C>T) is classified Uncertain significance in INTS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-14). AlphaMissense: ambiguous (0.5112); Ultra-rare (popmax 0.0203%, afr); Associated with Inborn genetic diseases.

What condition is associated with INTS1 p.Arg1867Trp (c.5599C>T)?

INTS1 p.Arg1867Trp (c.5599C>T) is associated with Inborn genetic diseases (ClinVar).

How common is INTS1 p.Arg1867Trp (c.5599C>T) in the general population?

INTS1 p.Arg1867Trp (c.5599C>T) is ultra-rare (popmax 0.0203%, afr) (gnomAD).

What do computational predictors say about INTS1 p.Arg1867Trp (c.5599C>T)?

AlphaMissense predicts ambiguous (score 0.5112) — an in-silico prediction, not a clinical call.

INTS1 p.Arg1867Trp

c.5599C>T · rs374803757 · VCV3110057

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5112 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0203%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5112	ambiguous
REVEL	0.622	indeterminate
SaProt	LLR -10.98	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP -1.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	27.6	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

Grpmax group 0.0203% African / African-American · 15/73,724 alleles

Filtering AF 0.0125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.01%

Overall 0.00422% 66/1,563,898 alleles · ultra-rare exomes 50/1,411,654 · genomes 16/152,244 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0203%	4,915
European (non-Finnish)	0.00381%	26,281
South Asian	0.00354%	28,273
Ashkenazi Jewishnot grpmax-eligible	0.00348%	28,772
Remaining individualsnot grpmax-eligible	0.0033%	30,317
East Asian	0.00238%	42,044

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.Arg1867Trp
Coding: c.5599C>T
MANE Select: NM_001080453
dbSNP: rs374803757
Type: single nucleotide variant
Location: chr7:1474742 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 1867: an α-helix; a UniProt-annotated variant site (in ndcagf; decreased protein abundance)

Full INTS1 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

INTS1 c.1283+5G>A Uncertain significance ★★ same condition
INTS1 c.2977-5C>T Uncertain significance ★★ same condition
INTS1 p.Ala1505Val Uncertain significance ★★ ⚠ same condition
INTS1 p.Ala1854Val Uncertain significance ★★ ⚠ same condition
INTS1 p.Ala2155Val Uncertain significance ★★ ⚠ same condition
INTS1 p.Ala2175Thr Uncertain significance ★★ ⚠ same condition
INTS1 p.Ala4Thr Uncertain significance ★★ ⚠ same condition
INTS1 p.Arg1096Cys 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/ints1-p-arg1867trp (accessed [today's date]).

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