Is INTS1 p.Val146Leu (c.436G>C) pathogenic?

INTS1 p.Val146Leu (c.436G>C) is classified Uncertain significance in INTS1 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-09-17). AlphaMissense: ambiguous (0.4157); Rare (popmax 0.134%, eas).

How common is INTS1 p.Val146Leu (c.436G>C) in the general population?

INTS1 p.Val146Leu (c.436G>C) is rare (popmax 0.134%, eas) (gnomAD).

What do computational predictors say about INTS1 p.Val146Leu (c.436G>C)?

AlphaMissense predicts ambiguous (score 0.4157) — an in-silico prediction, not a clinical call.

INTS1 p.Val146Leu

c.436G>C · rs182741272 · VCV3032064

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4157 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.134%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4157	ambiguous
REVEL	0.069	moderately benign-leaning
SaProt	LLR -5.88	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.3, phastCons 0.99
Regional constraint	o/e 0.96	unconstrained · MANE · 21 kb · p 0.12 · regional, not allelic
Overall
CADD	21.7	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 0.134% East Asian · 59/44,000 alleles

Filtering AF 0.107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0968%

Overall 0.00382% 61/1,596,498 alleles · rare exomes 50/1,444,144 · genomes 11/152,354 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.134%	746
Remaining individualsnot grpmax-eligible	0.00324%	30,901

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.Val146Leu
Coding: c.436G>C
MANE Select: NM_001080453
dbSNP: rs182741272
Type: single nucleotide variant
Location: chr7:1500280 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 146: an α-helix

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

Similar variants

INTS1 p.Val146Met Uncertain significance ★★ ⚠ same residue
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

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-val146leu (accessed [today's date]).

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