Is INTS1 p.Leu321= (c.963C>T) pathogenic?

INTS1 p.Leu321= (c.963C>T) is classified Likely benign in INTS1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-11). Rare (popmax 0.155%, afr); Associated with INTS1-related disorder.

What condition is associated with INTS1 p.Leu321= (c.963C>T)?

INTS1 p.Leu321= (c.963C>T) is associated with INTS1-related disorder (ClinVar).

How common is INTS1 p.Leu321= (c.963C>T) in the general population?

INTS1 p.Leu321= (c.963C>T) is rare (popmax 0.155%, afr) (gnomAD).

INTS1 p.Leu321=

c.963C>T · rs375867888 · VCV3045461

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.155%, afr)

Conditions

INTS1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.34	GERP -3
Overall
CADD	2.959	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.155% African / African-American · 116/74,944 alleles

Filtering AF 0.132% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.123%

Overall 0.00888% 143/1,610,024 alleles · rare exomes 82/1,457,790 · genomes 61/152,234 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.155%	646
Middle Eastern	0.053%	1,887
Remaining individualsnot grpmax-eligible	0.0145%	6,919
Admixed American	0.00834%	11,988
Finnishnot grpmax-eligible	0.0016%	62,436
European (non-Finnish)	0.000764%	130,947

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.Leu321=
Coding: c.963C>T
MANE Select: NM_001080453
dbSNP: rs375867888
Type: single nucleotide variant
Location: chr7:1499149 (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

INTS1-related disorder

Similar variants

INTS1 c.3156+8C>T Conflicting classifications of pathogenicity ★ same condition
INTS1 c.3850+76G>A Uncertain significance ★ same condition
INTS1 p.Gly73Ser Uncertain significance ⚠ same condition
INTS1 p.Lys435Asn Uncertain significance ⚠ same condition
INTS1 p.Met888Val Uncertain significance ⚠ same condition
INTS1 c.1138-4G>A Likely benign same condition
INTS1 c.2646+10G>A Likely benign same condition
INTS1 p.Ala1234= Likely benign 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-leu321 (accessed [today's date]).

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