Is INTS1 p.Arg2075Trp (c.6223C>T) pathogenic?

INTS1 p.Arg2075Trp (c.6223C>T) is classified Uncertain significance in INTS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-30). AlphaMissense: likely benign (0.1879); Ultra-rare (popmax 0.0149%, nfe); Associated with Inborn genetic diseases.

What condition is associated with INTS1 p.Arg2075Trp (c.6223C>T)?

INTS1 p.Arg2075Trp (c.6223C>T) is associated with Inborn genetic diseases (ClinVar).

How common is INTS1 p.Arg2075Trp (c.6223C>T) in the general population?

INTS1 p.Arg2075Trp (c.6223C>T) is ultra-rare (popmax 0.0149%, nfe) (gnomAD).

What do computational predictors say about INTS1 p.Arg2075Trp (c.6223C>T)?

AlphaMissense predicts likely benign (score 0.1879) — an in-silico prediction, not a clinical call.

INTS1 p.Arg2075Trp

c.6223C>T · rs201387183 · VCV3110061

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1879 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0149%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1879	likely benign
REVEL	0.189	benign-leaning
SaProt	LLR -8.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 1.5, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0149% European (non-Finnish) · 176/1,179,772 alleles

Filtering AF 0.0131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.0119% 192/1,612,194 alleles · ultra-rare exomes 180/1,460,108 · genomes 12/152,086 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0149%	6,703
Remaining individualsnot grpmax-eligible	0.00961%	10,408
East Asian	0.00669%	14,953
South Asian	0.00549%	18,216
Finnishnot grpmax-eligible	0.0016%	62,552
African / African-American	0.00134%	74,888

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.Arg2075Trp
Coding: c.6223C>T
MANE Select: NM_001080453
dbSNP: rs201387183
Type: single nucleotide variant
Location: chr7:1471603 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 2075: 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

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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-arg2075trp (accessed [today's date]).

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