Is INTS1 p.Pro1874Leu (c.5621C>T) pathogenic?

INTS1 p.Pro1874Leu (c.5621C>T) is classified Pathogenic in INTS1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-09-11). AlphaMissense: likely pathogenic (0.9307); Very rare (popmax 0.000346%, nfe); Associated with neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies.

What condition is associated with INTS1 p.Pro1874Leu (c.5621C>T)?

INTS1 p.Pro1874Leu (c.5621C>T) is associated with neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies (ClinVar).

How common is INTS1 p.Pro1874Leu (c.5621C>T) in the general population?

INTS1 p.Pro1874Leu (c.5621C>T) is very rare (popmax 0.000346%, nfe) (gnomAD).

What do computational predictors say about INTS1 p.Pro1874Leu (c.5621C>T)?

AlphaMissense predicts likely pathogenic (score 0.9307) — an in-silico prediction, not a clinical call.

INTS1 p.Pro1874Leu

c.5621C>T · rs1162809128 · VCV689523

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9307 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000346%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies

Computational evidence

Protein change
AlphaMissense	0.9307	likely pathogenic ✓ concordant with ClinVar
REVEL	0.604	indeterminate
SaProt	LLR -13.68	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
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	26.3	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 0.000346% European (non-Finnish) · 4/1,155,068 alleles

Filtering AF 8.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.5e-05%

Overall 0.00032% 5/1,561,546 alleles · very rare exomes 5/1,409,184 · genomes 0/152,362 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00165%	60,544
European (non-Finnish)grpmax	0.000346%	288,767

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1874Leu
Coding: c.5621C>T
MANE Select: NM_001080453
dbSNP: rs1162809128
Type: single nucleotide variant
Location: chr7:1474720 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 1874: an α-helix; a UniProt-annotated variant site (in ndcagf; decreased protein abundance); a UniProt-annotated variant site (in ndcagf; uncertain significance)

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

Disease context

neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

INTS1 c.3430-2A>C Likely pathogenic ★★ same condition
INTS1 p.Arg101Ter Likely pathogenic ★★ same condition
INTS1 c.1283+5G>A Uncertain significance ★★ same condition
INTS1 c.2977-5C>T Uncertain significance ★★ same condition
INTS1 p.Ala745Thr Uncertain significance ★★ ⚠ same condition
INTS1 p.Arg1130Cys Uncertain significance ★★ ⚠ same condition
INTS1 p.Arg1685Gln Uncertain significance ★★ ⚠ same condition
INTS1 p.Arg1800Gln 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-pro1874leu (accessed [today's date]).

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