Is INTS1 p.Pro1599Leu (c.4796C>T) pathogenic?

INTS1 p.Pro1599Leu (c.4796C>T) is classified Likely benign in INTS1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-08-13). AlphaMissense: likely benign (0.0732); Rare (popmax 0.498%, afr); Associated with INTS1-related disorder.

What condition is associated with INTS1 p.Pro1599Leu (c.4796C>T)?

INTS1 p.Pro1599Leu (c.4796C>T) is associated with INTS1-related disorder (ClinVar).

How common is INTS1 p.Pro1599Leu (c.4796C>T) in the general population?

INTS1 p.Pro1599Leu (c.4796C>T) is rare (popmax 0.498%, afr) (gnomAD).

What do computational predictors say about INTS1 p.Pro1599Leu (c.4796C>T)?

AlphaMissense predicts likely benign (score 0.0732) — an in-silico prediction, not a clinical call.

INTS1 p.Pro1599Leu

c.4796C>T · rs147391129 · VCV3052753

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0732 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.498%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

INTS1-related disorder

Computational evidence

Protein change
AlphaMissense	0.0732	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -6.94	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 1.1	GERP -2.4, phastCons 0.86
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	5.309	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 0.498% African / African-American · 374/75,052 alleles

Filtering AF 0.457% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.44%

Overall 0.0418% 674/1,612,338 alleles · rare exomes 437/1,460,000 · genomes 237/152,338 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.498%	201
Remaining individualsnot grpmax-eligible	0.0817%	1,224
Admixed American	0.0517%	1,935
Middle Eastern	0.0497%	2,012
European (non-Finnish)	0.0179%	5,591
South Asian	0.00329%	30,357
Finnishnot grpmax-eligible	0.0016%	62,612

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.Pro1599Leu
Coding: c.4796C>T
MANE Select: NM_001080453
dbSNP: rs147391129
Type: single nucleotide variant
Location: chr7:1477771 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 1599: an α-helix

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

Disease context

INTS1-related disorder

Similar variants

INTS1 c.3156+8C>T Conflicting classifications of pathogenicity ★ same condition
INTS1 c.3850+76G>A Uncertain significance ★ same condition
INTS1 p.Gly73Ser Uncertain significance ⚠ same condition
INTS1 p.Lys435Asn Uncertain significance ⚠ same condition
INTS1 p.Met888Val Uncertain significance ⚠ same condition
INTS1 c.1138-4G>A Likely benign same condition
INTS1 c.2646+10G>A Likely benign same condition
INTS1 p.Ala1234= Likely benign 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-pro1599leu (accessed [today's date]).

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