Is INTS1 p.Arg2100Cys (c.6298C>T) pathogenic?

INTS1 p.Arg2100Cys (c.6298C>T) is classified Uncertain significance in INTS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-16). AlphaMissense: likely pathogenic (0.6829); Very rare (popmax 0.00394%, nfe); Associated with Inborn genetic diseases.

What condition is associated with INTS1 p.Arg2100Cys (c.6298C>T)?

INTS1 p.Arg2100Cys (c.6298C>T) is associated with Inborn genetic diseases (ClinVar).

How common is INTS1 p.Arg2100Cys (c.6298C>T) in the general population?

INTS1 p.Arg2100Cys (c.6298C>T) is very rare (popmax 0.00394%, nfe) (gnomAD).

What do computational predictors say about INTS1 p.Arg2100Cys (c.6298C>T)?

AlphaMissense predicts likely pathogenic (score 0.6829) — an in-silico prediction, not a clinical call.

INTS1 p.Arg2100Cys

c.6298C>T · VCV4275832

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6829 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00394%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6829	likely pathogenic
REVEL	0.612	indeterminate
SaProt	LLR -8.06	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	31.0	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 0.00394% European (non-Finnish) · 46/1,167,044 alleles

Filtering AF 0.00302% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0027%

Overall 0.00334% 53/1,584,554 alleles · very rare exomes 44/1,432,344 · genomes 9/152,210 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00652%	15,347
European (non-Finnish)grpmax	0.00394%	25,371
East Asian	0.00232%	43,180
African / African-American	0.00134%	74,364
South Asian	0.00116%	86,528

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.Arg2100Cys
Coding: c.6298C>T
MANE Select: NM_001080453
Type: single nucleotide variant
Location: chr7:1471182 (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.Arg2100His 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-arg2100cys (accessed [today's date]).

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