Is INTS1 p.Val1128Met (c.3382G>A) pathogenic?

INTS1 p.Val1128Met (c.3382G>A) is classified Benign in INTS1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-08-13). AlphaMissense: likely benign (0.3012); Ultra-rare (popmax 0.0133%, afr); Associated with INTS1-related disorder.

What condition is associated with INTS1 p.Val1128Met (c.3382G>A)?

INTS1 p.Val1128Met (c.3382G>A) is associated with INTS1-related disorder (ClinVar).

How common is INTS1 p.Val1128Met (c.3382G>A) in the general population?

INTS1 p.Val1128Met (c.3382G>A) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

What do computational predictors say about INTS1 p.Val1128Met (c.3382G>A)?

AlphaMissense predicts likely benign (score 0.3012) — an in-silico prediction, not a clinical call.

INTS1 p.Val1128Met

c.3382G>A · rs200985889 · VCV3052788

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3012 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

INTS1-related disorder

Computational evidence

Protein change
AlphaMissense	0.3012	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -7.97	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 4.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 21 kb · p 0.12 · regional, not allelic
Overall
CADD	23.8	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 0.0133% African / African-American · 10/74,928 alleles

Filtering AF 0.00986% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00921%

Overall 0.0244% 393/1,612,216 alleles · ultra-rare exomes 350/1,459,996 · genomes 43/152,220 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.679%	147
Remaining individualsnot grpmax-eligible	0.0481%	2,081
Finnishnot grpmax-eligible	0.0224%	4,473
African / African-Americangrpmax	0.0133%	7,493
European (non-Finnish)	0.0114%	8,739
Admixed American	0.00333%	29,995
South Asian	0.0011%	91,094

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val1128Met
Coding: c.3382G>A
MANE Select: NM_001080453
dbSNP: rs200985889
Type: single nucleotide variant
Location: chr7:1484050 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 1128: an α-helix

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-val1128met (accessed [today's date]).

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