Is INTS1 p.Arg2100His (c.6299G>A) pathogenic?

INTS1 p.Arg2100His (c.6299G>A) is classified Uncertain significance in INTS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: likely pathogenic (0.8609); Very rare (popmax 0.00797%, nfe); Associated with Inborn genetic diseases.

What condition is associated with INTS1 p.Arg2100His (c.6299G>A)?

INTS1 p.Arg2100His (c.6299G>A) is associated with Inborn genetic diseases (ClinVar).

How common is INTS1 p.Arg2100His (c.6299G>A) in the general population?

INTS1 p.Arg2100His (c.6299G>A) is very rare (popmax 0.00797%, nfe) (gnomAD).

What do computational predictors say about INTS1 p.Arg2100His (c.6299G>A)?

AlphaMissense predicts likely pathogenic (score 0.8609) — an in-silico prediction, not a clinical call.

INTS1 p.Arg2100His

c.6299G>A · VCV3286185

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8609 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00797%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8609	likely pathogenic
REVEL	0.688	pathogenic-leaning
SaProt	LLR -8.56	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	29.5	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 0.00797% European (non-Finnish) · 93/1,166,746 alleles

Filtering AF 0.00663% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00615%

Overall 0.00657% 104/1,584,000 alleles · very rare exomes 99/1,431,794 · genomes 5/152,206 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00797%	12,546
South Asian	0.00578%	17,293
Admixed American	0.00357%	28,036
Remaining individualsnot grpmax-eligible	0.00326%	30,680
East Asian	0.00232%	43,178
African / African-American	0.00135%	74,332

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.Arg2100His
Coding: c.6299G>A
MANE Select: NM_001080453
Type: single nucleotide variant
Location: chr7:1471181 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 2100: an α-helix; a UniProt-annotated variant site (in ndcagf; decreased protein abundance); a UniProt-annotated variant site (in ndcagf)

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.Arg2100Cys Uncertain significance ★ ⚠ 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-arg2100his (accessed [today's date]).

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