Is INTS1 p.Arg1004Trp (c.3010C>T) pathogenic?

INTS1 p.Arg1004Trp (c.3010C>T) is classified Uncertain significance in INTS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-01). AlphaMissense: likely benign (0.0981); Very rare (popmax 0.00833%, amr); Associated with neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies.

What condition is associated with INTS1 p.Arg1004Trp (c.3010C>T)?

INTS1 p.Arg1004Trp (c.3010C>T) is associated with neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies (ClinVar).

How common is INTS1 p.Arg1004Trp (c.3010C>T) in the general population?

INTS1 p.Arg1004Trp (c.3010C>T) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about INTS1 p.Arg1004Trp (c.3010C>T)?

AlphaMissense predicts likely benign (score 0.0981) — an in-silico prediction, not a clinical call.

INTS1 p.Arg1004Trp

c.3010C>T · rs200531046 · VCV2663789

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0981 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies

Computational evidence

Protein change
AlphaMissense	0.0981	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -9.10	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 3.8	GERP 0.22, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 21 kb · p 0.12 · regional, not allelic
Overall
CADD	26.2	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 0.00833% Admixed American · 5/59,996 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00397% 64/1,612,512 alleles · very rare exomes 62/1,460,352 · genomes 2/152,160 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	11,999
European (non-Finnish)	0.00441%	22,689
South Asian	0.00439%	22,769
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
Remaining individualsnot grpmax-eligible	0.0032%	31,220

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.Arg1004Trp
Coding: c.3010C>T
MANE Select: NM_001080453
dbSNP: rs200531046
Type: single nucleotide variant
Location: chr7:1485436 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB

Full INTS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

INTS1 p.Arg1004Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
INTS1 c.3430-2A>C Likely pathogenic ★★ same condition
INTS1 p.Arg101Ter Likely pathogenic ★★ same condition
INTS1 c.1283+5G>A Uncertain significance ★★ same condition
INTS1 c.2977-5C>T Uncertain significance ★★ same condition
INTS1 p.Ala745Thr Uncertain significance ★★ ⚠ same condition
INTS1 p.Arg1130Cys Uncertain significance ★★ ⚠ same condition
INTS1 p.Arg1685Gln 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-arg1004trp (accessed [today's date]).

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