Is INTS1 p.Asp1233Glu (c.3699C>G) pathogenic?

INTS1 p.Asp1233Glu (c.3699C>G) is classified Uncertain significance in INTS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-14). AlphaMissense: ambiguous (0.4475); Ultra-rare (popmax 0.0107%, nfe).

How common is INTS1 p.Asp1233Glu (c.3699C>G) in the general population?

INTS1 p.Asp1233Glu (c.3699C>G) is ultra-rare (popmax 0.0107%, nfe) (gnomAD).

What do computational predictors say about INTS1 p.Asp1233Glu (c.3699C>G)?

AlphaMissense predicts ambiguous (score 0.4475) — an in-silico prediction, not a clinical call.

INTS1 p.Asp1233Glu

c.3699C>G · VCV3365505

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4475 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4475	ambiguous
REVEL	0.315	indeterminate
SaProt	LLR -7.00	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -11	GERP -2.3
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	0.147	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 0.0107% European (non-Finnish) · 126/1,175,978 alleles

Filtering AF 0.00914% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00858%

Overall 0.0216% 347/1,607,068 alleles · ultra-rare exomes 312/1,454,714 · genomes 35/152,354 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.346%	289
European (non-Finnish)grpmax	0.0107%	9,333
Remaining individualsnot grpmax-eligible	0.00483%	20,715
Admixed American	0.00168%	59,666

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.Asp1233Glu
Coding: c.3699C>G
MANE Select: NM_001080453
Type: single nucleotide variant
Location: chr7:1482550 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 1233: an α-helix

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

Similar variants

INTS1 p.Asp1233= Likely benign same residue
INTS1 c.3430-2A>C Likely pathogenic ★★ same type
INTS1 p.Arg101Ter Likely pathogenic ★★ same type
INTS1 p.Glu182Ter Likely pathogenic ★★ same type
INTS1 c.1283+5G>A Uncertain significance ★★ same type
INTS1 c.2977-5C>T Uncertain significance ★★ same type
INTS1 p.Ala1112Val Uncertain significance ★★ ⚠ same type
INTS1 p.Ala1505Val Uncertain significance ★★ ⚠ same type

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-asp1233glu (accessed [today's date]).

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