Is INTS1 p.Pro1811Leu (c.5432C>T) pathogenic?

INTS1 p.Pro1811Leu (c.5432C>T) is classified Uncertain significance in INTS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-11). AlphaMissense: ambiguous (0.4866); Ultra-rare (popmax 0.0147%, eas); Associated with Inborn genetic diseases.

What condition is associated with INTS1 p.Pro1811Leu (c.5432C>T)?

INTS1 p.Pro1811Leu (c.5432C>T) is associated with Inborn genetic diseases (ClinVar).

How common is INTS1 p.Pro1811Leu (c.5432C>T) in the general population?

INTS1 p.Pro1811Leu (c.5432C>T) is ultra-rare (popmax 0.0147%, eas) (gnomAD).

What do computational predictors say about INTS1 p.Pro1811Leu (c.5432C>T)?

AlphaMissense predicts ambiguous (score 0.4866) — an in-silico prediction, not a clinical call.

INTS1 p.Pro1811Leu

c.5432C>T · rs749007520 · VCV2592485

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4866 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4866	ambiguous
REVEL	0.719	pathogenic-leaning
SaProt	LLR -7.51	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	28.7	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 0.0147% East Asian · 6/40,910 alleles

Filtering AF 0.0064% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00487%

Overall 0.00181% 28/1,545,794 alleles · ultra-rare exomes 24/1,393,608 · genomes 4/152,186 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0147%	6,818
South Asian	0.0119%	8,403
Admixed American	0.00588%	16,993
Remaining individualsnot grpmax-eligible	0.005%	19,994
European (non-Finnish)	0.000523%	191,121

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.Pro1811Leu
Coding: c.5432C>T
MANE Select: NM_001080453
dbSNP: rs749007520
Type: single nucleotide variant
Location: chr7:1476018 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 1811: 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-pro1811leu (accessed [today's date]).

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