Is INTS1 p.Pro383Leu (c.1148C>T) pathogenic?

INTS1 p.Pro383Leu (c.1148C>T) is classified Uncertain significance in INTS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: ambiguous (0.4809); Very rare (popmax 0.00225%, sas); Associated with Inborn genetic diseases.

What condition is associated with INTS1 p.Pro383Leu (c.1148C>T)?

INTS1 p.Pro383Leu (c.1148C>T) is associated with Inborn genetic diseases (ClinVar).

How common is INTS1 p.Pro383Leu (c.1148C>T) in the general population?

INTS1 p.Pro383Leu (c.1148C>T) is very rare (popmax 0.00225%, sas) (gnomAD).

What do computational predictors say about INTS1 p.Pro383Leu (c.1148C>T)?

AlphaMissense predicts ambiguous (score 0.4809) — an in-silico prediction, not a clinical call.

INTS1 p.Pro383Leu

c.1148C>T · rs376069725 · VCV2591870

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4809 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00225%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4809	ambiguous
REVEL	0.335	indeterminate
SaProt	LLR -6.45	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 21 kb · p 0.12 · regional, not allelic
Overall
CADD	28.9	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 0.00225% South Asian · 2/88,722 alleles

Filtering AF 0.000881% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00072%

Overall 0.00125% 20/1,603,708 alleles · very rare exomes 18/1,451,642 · genomes 2/152,066 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00225%	44,361
East Asian	0.00225%	44,476
European (non-Finnish)	0.00145%	69,173

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.Pro383Leu
Coding: c.1148C>T
MANE Select: NM_001080453
dbSNP: rs376069725
Type: single nucleotide variant
Location: chr7:1498842 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 383: an α-helix

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.Pro383Thr Uncertain significance ★ 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-pro383leu (accessed [today's date]).

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