Is INTS1 p.Glu1387Gln (c.4159G>C) pathogenic?

INTS1 p.Glu1387Gln (c.4159G>C) is classified Uncertain significance in INTS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-24). AlphaMissense: likely pathogenic (0.6099); Very rare (popmax 0.00316%, nfe); Associated with Inborn genetic diseases.

What condition is associated with INTS1 p.Glu1387Gln (c.4159G>C)?

INTS1 p.Glu1387Gln (c.4159G>C) is associated with Inborn genetic diseases (ClinVar).

How common is INTS1 p.Glu1387Gln (c.4159G>C) in the general population?

INTS1 p.Glu1387Gln (c.4159G>C) is very rare (popmax 0.00316%, nfe) (gnomAD).

What do computational predictors say about INTS1 p.Glu1387Gln (c.4159G>C)?

AlphaMissense predicts likely pathogenic (score 0.6099) — an in-silico prediction, not a clinical call.

INTS1 p.Glu1387Gln

c.4159G>C · rs767012416 · VCV2336214

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6099 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00316%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6099	likely pathogenic
REVEL	0.183	benign-leaning
SaProt	LLR -6.60	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.4, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	25.4	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 0.00316% European (non-Finnish) · 36/1,140,456 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00205%

Overall 0.00254% 39/1,537,002 alleles · very rare exomes 30/1,384,754 · genomes 9/152,248 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00316%	31,679
African / African-American	0.00275%	36,398
Remaining individualsnot grpmax-eligible	0.00168%	59,506

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.Glu1387Gln
Coding: c.4159G>C
MANE Select: NM_001080453
dbSNP: rs767012416
Type: single nucleotide variant
Location: chr7:1479600 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 1387: 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-glu1387gln (accessed [today's date]).

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