Is INTS2 p.Arg410Cys (c.1228C>T) pathogenic?

INTS2 p.Arg410Cys (c.1228C>T) is classified Uncertain significance in INTS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-16). AlphaMissense: likely benign (0.2919); Very rare (popmax 0.00365%, nfe).

How common is INTS2 p.Arg410Cys (c.1228C>T) in the general population?

INTS2 p.Arg410Cys (c.1228C>T) is very rare (popmax 0.00365%, nfe) (gnomAD).

What do computational predictors say about INTS2 p.Arg410Cys (c.1228C>T)?

AlphaMissense predicts likely benign (score 0.2919) — an in-silico prediction, not a clinical call.

INTS2 p.Arg410Cys

c.1228C>T · VCV4275942

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2919 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00365%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2919	likely benign
REVEL	0.396	indeterminate
SaProt	LLR -7.93	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 59 kb · p 6.2e-09 · regional, not allelic
Overall
CADD	29.8	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R418C vs ClinVar R410C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00365% European (non-Finnish) · 43/1,178,834 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00279% 45/1,612,100 alleles · very rare exomes 43/1,459,934 · genomes 2/152,166 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00365%	27,415
East Asian	0.00223%	44,872
South Asian	0.0011%	90,760

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: INTS2
Protein: p.Arg410Cys
Coding: c.1228C>T
MANE Select: NM_001351695
Type: single nucleotide variant
Location: chr17:61904539 (GRCh38)
Gene constraint: LOEUF 0.491 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 78.90 · 8 PDB
Residue 418 UniProt numbering: an α-helix

Full INTS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

INTS2 p.Arg410His Uncertain significance ★ ⚠ same residue
INTS2 c.-17A>G Uncertain significance ★ ⚠ same type
INTS2 c.-1A>G Uncertain significance ★ ⚠ same type
INTS2 c.-3A>G Uncertain significance ★ ⚠ same type
INTS2 p.Ala1125Ser Uncertain significance ★ ⚠ same type
INTS2 p.Ala379Val Uncertain significance ★ same type
INTS2 p.Ala400Asp Uncertain significance ★ ⚠ same type
INTS2 p.Ala57Val Uncertain significance ★ ⚠ same type

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/ints2-p-arg410cys (accessed [today's date]).

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