Is INTS2 p.Leu337Val (c.1009C>G) pathogenic?

INTS2 p.Leu337Val (c.1009C>G) is classified Uncertain significance in INTS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-15). AlphaMissense: likely benign (0.0924); Very rare (popmax 0.00134%, afr).

How common is INTS2 p.Leu337Val (c.1009C>G) in the general population?

INTS2 p.Leu337Val (c.1009C>G) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about INTS2 p.Leu337Val (c.1009C>G)?

AlphaMissense predicts likely benign (score 0.0924) — an in-silico prediction, not a clinical call.

INTS2 p.Leu337Val

c.1009C>G · rs369992812 · VCV2249450

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0924 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0924	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -6.38	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 4.4	GERP 1.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 59 kb · p 6.2e-09 · regional, not allelic
Overall
CADD	17.52	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 L345V vs ClinVar L337V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,686 alleles

Filtering AF 0.000362% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000262%

Overall 0.000628% 10/1,592,940 alleles · very rare exomes 8/1,440,792 · genomes 2/152,148 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,686
European (non-Finnish)	0.00077%	129,902

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.Leu337Val
Coding: c.1009C>G
MANE Select: NM_001351695
dbSNP: rs369992812
Type: single nucleotide variant
Location: chr17:61907580 (GRCh38)
Gene constraint: LOEUF 0.491 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 78.90 · 8 PDB
Residue 345 UniProt numbering: an α-helix

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

Similar variants

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
INTS2 p.Ala599Val 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-leu337val (accessed [today's date]).

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