Is INTS1 p.Arg1841Cys (c.5521C>T) pathogenic?

INTS1 p.Arg1841Cys (c.5521C>T) is classified Uncertain significance in INTS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-22). AlphaMissense: likely benign (0.3371); Very rare (popmax 0.00806%, afr); Associated with neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies.

What condition is associated with INTS1 p.Arg1841Cys (c.5521C>T)?

INTS1 p.Arg1841Cys (c.5521C>T) is associated with neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies (ClinVar).

How common is INTS1 p.Arg1841Cys (c.5521C>T) in the general population?

INTS1 p.Arg1841Cys (c.5521C>T) is very rare (popmax 0.00806%, afr) (gnomAD).

What do computational predictors say about INTS1 p.Arg1841Cys (c.5521C>T)?

AlphaMissense predicts likely benign (score 0.3371) — an in-silico prediction, not a clinical call.

INTS1 p.Arg1841Cys

c.5521C>T · rs368503457 · VCV1328176

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3371 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00806%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies

Computational evidence

Protein change
AlphaMissense	0.3371	likely benign
REVEL	0.326	indeterminate
SaProt	LLR -7.65	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.75 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	28.2	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 0.00806% African / African-American · 6/74,474 alleles

Filtering AF 0.00349% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0024%

Overall 0.00126% 20/1,590,034 alleles · very rare exomes 14/1,437,816 · genomes 6/152,218 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00806%	12,412
East Asian	0.00229%	43,756
Admixed American	0.00175%	57,250
Remaining individualsnot grpmax-eligible	0.00163%	61,486
European (non-Finnish)	0.00094%	106,437

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.Arg1841Cys
Coding: c.5521C>T
MANE Select: NM_001080453
dbSNP: rs368503457
Type: single nucleotide variant
Location: chr7:1474820 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 1841: an α-helix; a UniProt-annotated variant site (in ndcagf; decreased protein abundance)

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.Arg1841His 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-arg1841cys (accessed [today's date]).

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