Is INTS2 p.Pro940Leu (c.2819C>T) pathogenic?

INTS2 p.Pro940Leu (c.2819C>T) is classified Uncertain significance in INTS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely benign (0.1823); Ultra-rare (popmax 0.0133%, amr).

How common is INTS2 p.Pro940Leu (c.2819C>T) in the general population?

INTS2 p.Pro940Leu (c.2819C>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about INTS2 p.Pro940Leu (c.2819C>T)?

AlphaMissense predicts likely benign (score 0.1823) — an in-silico prediction, not a clinical call.

INTS2 p.Pro940Leu

c.2819C>T · VCV4275940

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1823 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1823	likely benign
REVEL	0.262	benign-leaning
SaProt	LLR -8.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 59 kb · p 6.2e-09 · regional, not allelic
Overall
CADD	24.3	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 P948L vs ClinVar P940L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/60,010 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.000868% 14/1,613,522 alleles · ultra-rare exomes 4/1,461,278 · genomes 10/152,244 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,501
Remaining individualsnot grpmax-eligible	0.0064%	15,619
African / African-American	0.00267%	37,503

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.Pro940Leu
Coding: c.2819C>T
MANE Select: NM_001351695
Type: single nucleotide variant
Location: chr17:61869948 (GRCh38)
Gene constraint: LOEUF 0.491 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 78.90 · 8 PDB

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

Similar variants

INTS2 p.Pro940Arg 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-pro940leu (accessed [today's date]).

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