Is INTS1 p.Arg1004Pro (c.3011G>C) pathogenic?

INTS1 p.Arg1004Pro (c.3011G>C) is classified Conflicting classifications of pathogenicity in INTS1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-10-22). AlphaMissense: likely benign (0.1633); Ultra-rare (popmax 0.0495%, mid); Associated with neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies.

What condition is associated with INTS1 p.Arg1004Pro (c.3011G>C)?

INTS1 p.Arg1004Pro (c.3011G>C) is associated with neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies (ClinVar).

How common is INTS1 p.Arg1004Pro (c.3011G>C) in the general population?

INTS1 p.Arg1004Pro (c.3011G>C) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about INTS1 p.Arg1004Pro (c.3011G>C)?

AlphaMissense predicts likely benign (score 0.1633) — an in-silico prediction, not a clinical call.

INTS1 p.Arg1004Pro

c.3011G>C · rs200828819 · VCV1687712

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1633 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies

Computational evidence

Protein change
AlphaMissense	0.1633	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -5.99	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 4.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 21 kb · p 0.12 · regional, not allelic
Overall
CADD	23.9	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 0.0495% Middle Eastern · 3/6,062 alleles

Filtering AF 0.0205% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0195%

Overall 0.0182% 294/1,612,760 alleles · ultra-rare exomes 270/1,460,432 · genomes 24/152,328 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,021
European (non-Finnish)	0.0227%	4,402
Remaining individualsnot grpmax-eligible	0.0208%	4,805
African / African-American	0.00666%	15,012
Admixed American	0.00333%	30,011
South Asian	0.00329%	30,362

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.Arg1004Pro
Coding: c.3011G>C
MANE Select: NM_001080453
dbSNP: rs200828819
Type: single nucleotide variant
Location: chr7:1485435 (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.Arg1004Trp Uncertain significance ★ ⚠ 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-arg1004pro (accessed [today's date]).

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