Is INTS1 p.Leu1357Phe (c.4069C>T) pathogenic?

INTS1 p.Leu1357Phe (c.4069C>T) is classified Uncertain significance in INTS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-03). AlphaMissense: likely benign (0.2733); Ultra-rare (popmax 0.0895%, eas).

How common is INTS1 p.Leu1357Phe (c.4069C>T) in the general population?

INTS1 p.Leu1357Phe (c.4069C>T) is ultra-rare (popmax 0.0895%, eas) (gnomAD).

What do computational predictors say about INTS1 p.Leu1357Phe (c.4069C>T)?

AlphaMissense predicts likely benign (score 0.2733) — an in-silico prediction, not a clinical call.

INTS1 p.Leu1357Phe

c.4069C>T · VCV4055893

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2733 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0895%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2733	likely benign
REVEL	0.229	benign-leaning
SaProt	LLR -10.70	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	Δ0.22	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 4.4	GERP 1.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0895% East Asian · 40/44,684 alleles

Filtering AF 0.0676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0598%

Overall 0.00355% 57/1,607,258 alleles · ultra-rare exomes 45/1,454,912 · genomes 12/152,346 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0895%	1,117
Remaining individualsnot grpmax-eligible	0.00805%	12,422
South Asian	0.0011%	90,684
European (non-Finnish)	0.000934%	107,012

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.Leu1357Phe
Coding: c.4069C>T
MANE Select: NM_001080453
Type: single nucleotide variant
Location: chr7:1480322 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 1357: an α-helix

Full INTS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

INTS1 c.3430-2A>C Likely pathogenic ★★ same type
INTS1 p.Arg101Ter Likely pathogenic ★★ same type
INTS1 p.Glu182Ter Likely pathogenic ★★ same type
INTS1 c.1283+5G>A Uncertain significance ★★ same type
INTS1 c.2977-5C>T Uncertain significance ★★ same type
INTS1 p.Ala1112Val Uncertain significance ★★ ⚠ same type
INTS1 p.Ala1505Val Uncertain significance ★★ ⚠ same type
INTS1 p.Ala1854Val 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/ints1-p-leu1357phe (accessed [today's date]).

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