Is INTS1 p.Pro1109Leu (c.3326C>T) pathogenic?

INTS1 p.Pro1109Leu (c.3326C>T) is classified Likely benign in INTS1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-01). AlphaMissense: likely benign (0.0922); Rare (popmax 0.273%, nfe).

How common is INTS1 p.Pro1109Leu (c.3326C>T) in the general population?

INTS1 p.Pro1109Leu (c.3326C>T) is rare (popmax 0.273%, nfe) (gnomAD).

What do computational predictors say about INTS1 p.Pro1109Leu (c.3326C>T)?

AlphaMissense predicts likely benign (score 0.0922) — an in-silico prediction, not a clinical call.

INTS1 p.Pro1109Leu

c.3326C>T · rs200983063 · VCV2657199

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0922 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.273%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0922	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -7.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.8	GERP -1.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 21 kb · p 0.12 · regional, not allelic
Overall
CADD	16.44	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 0.273% European (non-Finnish) · 3,219/1,179,760 alleles

Filtering AF 0.265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.262%

Overall 0.222% 3,576/1,612,484 alleles · rare exomes 3,330/1,460,188 · genomes 246/152,296 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.273%	366
Remaining individualsnot grpmax-eligible	0.199%	504
Admixed American	0.11%	909
African / African-American	0.1%	1,000
Finnishnot grpmax-eligible	0.0686%	1,458
South Asian	0.0527%	1,898
East Asian	0.00223%	44,870

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.Pro1109Leu
Coding: c.3326C>T
MANE Select: NM_001080453
dbSNP: rs200983063
Type: single nucleotide variant
Location: chr7:1484106 (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 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
INTS1 p.Ala1854Val 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-pro1109leu (accessed [today's date]).

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