Is INTS1 p.Leu998Ile (c.2992C>A) pathogenic?

INTS1 p.Leu998Ile (c.2992C>A) is classified Uncertain significance in INTS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-11). AlphaMissense: ambiguous (0.3835); Very rare (popmax 0.000509%, nfe); Associated with Inborn genetic diseases.

What condition is associated with INTS1 p.Leu998Ile (c.2992C>A)?

INTS1 p.Leu998Ile (c.2992C>A) is associated with Inborn genetic diseases (ClinVar).

How common is INTS1 p.Leu998Ile (c.2992C>A) in the general population?

INTS1 p.Leu998Ile (c.2992C>A) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about INTS1 p.Leu998Ile (c.2992C>A)?

AlphaMissense predicts ambiguous (score 0.3835) — an in-silico prediction, not a clinical call.

INTS1 p.Leu998Ile

c.2992C>A · rs745365894 · VCV1474696

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3835 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3835	ambiguous
REVEL	0.097	moderately benign-leaning
SaProt	LLR -8.39	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.2	GERP 1.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 21 kb · p 0.12 · regional, not allelic
Overall
CADD	24.4	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 0.000509% European (non-Finnish) · 6/1,179,826 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00304% 49/1,612,324 alleles · very rare exomes 39/1,460,082 · genomes 10/152,242 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0671%	1,489
Remaining individualsnot grpmax-eligible	0.0016%	62,434
European (non-Finnish)grpmax	0.000509%	196,637

Finnish 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.Leu998Ile
Coding: c.2992C>A
MANE Select: NM_001080453
dbSNP: rs745365894
Type: single nucleotide variant
Location: chr7:1485454 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 998: 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 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-leu998ile (accessed [today's date]).

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