Is INTS1 p.Arg1427His (c.4280G>A) pathogenic?

INTS1 p.Arg1427His (c.4280G>A) is classified Conflicting classifications of pathogenicity in INTS1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-07-05). AlphaMissense: likely benign (0.0689); Ultra-rare (popmax 0.0108%, amr); Associated with Inborn genetic diseases.

What condition is associated with INTS1 p.Arg1427His (c.4280G>A)?

INTS1 p.Arg1427His (c.4280G>A) is associated with Inborn genetic diseases (ClinVar).

How common is INTS1 p.Arg1427His (c.4280G>A) in the general population?

INTS1 p.Arg1427His (c.4280G>A) is ultra-rare (popmax 0.0108%, amr) (gnomAD).

What do computational predictors say about INTS1 p.Arg1427His (c.4280G>A)?

AlphaMissense predicts likely benign (score 0.0689) — an in-silico prediction, not a clinical call.

INTS1 p.Arg1427His

c.4280G>A · rs373326766 · VCV2657191

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0689 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0108%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0689	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -7.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.38	GERP 0.12, phastCons 0.032
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	15.58	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 0.0108% Admixed American · 6/55,424 alleles

Filtering AF 0.00468% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00401%

Overall 0.00545% 86/1,577,652 alleles · ultra-rare exomes 73/1,425,266 · genomes 13/152,386 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0131%	7,643
Admixed Americangrpmax	0.0108%	9,237
European (non-Finnish)	0.0055%	18,171
African / African-American	0.00404%	24,759
South Asian	0.00349%	28,618
Ashkenazi Jewishnot grpmax-eligible	0.00346%	28,926
East Asian	0.00233%	42,896

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.Arg1427His
Coding: c.4280G>A
MANE Select: NM_001080453
dbSNP: rs373326766
Type: single nucleotide variant
Location: chr7:1479479 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 1427: 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 p.Arg1427Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-arg1427his (accessed [today's date]).

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