Is INTS1 p.Pro1364Leu (c.4091C>T) pathogenic?

INTS1 p.Pro1364Leu (c.4091C>T) is classified Uncertain significance in INTS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-11). AlphaMissense: likely benign (0.0993); Ultra-rare (popmax 0.0103%, amr); Associated with Inborn genetic diseases.

What condition is associated with INTS1 p.Pro1364Leu (c.4091C>T)?

INTS1 p.Pro1364Leu (c.4091C>T) is associated with Inborn genetic diseases (ClinVar).

How common is INTS1 p.Pro1364Leu (c.4091C>T) in the general population?

INTS1 p.Pro1364Leu (c.4091C>T) is ultra-rare (popmax 0.0103%, amr) (gnomAD).

What do computational predictors say about INTS1 p.Pro1364Leu (c.4091C>T)?

AlphaMissense predicts likely benign (score 0.0993) — an in-silico prediction, not a clinical call.

INTS1 p.Pro1364Leu

c.4091C>T · VCV3371698

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0993 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0993	likely benign
REVEL	0.215	benign-leaning
SaProt	LLR -8.26	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 12	GERP 1.4, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	24.5	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 0.0103% Admixed American · 4/38,974 alleles

Filtering AF 0.00349% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00239%

Overall 0.00326% 48/1,471,342 alleles · ultra-rare exomes 43/1,319,096 · genomes 5/152,246 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0103%	9,743
European (non-Finnish)	0.0036%	27,752
Remaining individualsnot grpmax-eligible	0.00353%	28,349
South Asian	0.00275%	36,356

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.Pro1364Leu
Coding: c.4091C>T
MANE Select: NM_001080453
Type: single nucleotide variant
Location: chr7:1479668 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

INTS1 p.Pro1364= Conflicting classifications of pathogenicity ★ same residue
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

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-pro1364leu (accessed [today's date]).

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