Is INTS1 p.Val275Ile (c.823G>A) pathogenic?

INTS1 p.Val275Ile (c.823G>A) is classified Uncertain significance in INTS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-29). AlphaMissense: likely benign (0.0795); Ultra-rare (popmax 0.0496%, afr); Associated with Inborn genetic diseases.

What condition is associated with INTS1 p.Val275Ile (c.823G>A)?

INTS1 p.Val275Ile (c.823G>A) is associated with Inborn genetic diseases (ClinVar).

How common is INTS1 p.Val275Ile (c.823G>A) in the general population?

INTS1 p.Val275Ile (c.823G>A) is ultra-rare (popmax 0.0496%, afr) (gnomAD).

What do computational predictors say about INTS1 p.Val275Ile (c.823G>A)?

AlphaMissense predicts likely benign (score 0.0795) — an in-silico prediction, not a clinical call.

INTS1 p.Val275Ile

c.823G>A · VCV4038933

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0795 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0496%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0795	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -7.79	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 -1.1	GERP -1.6
Regional constraint	o/e 0.96	unconstrained · MANE · 21 kb · p 0.12 · regional, not allelic
Overall
CADD	6.032	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0496% African / African-American · 37/74,634 alleles

Filtering AF 0.037% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0326%

Overall 0.00455% 73/1,602,752 alleles · ultra-rare exomes 53/1,451,120 · genomes 20/151,632 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0496%	2,017
European (non-Finnish)	0.00281%	35,610
Admixed American	0.00172%	58,302
Remaining individualsnot grpmax-eligible	0.00161%	62,006
South Asian	0.00111%	89,966

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.Val275Ile
Coding: c.823G>A
MANE Select: NM_001080453
Type: single nucleotide variant
Location: chr7:1499494 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

INTS1 c.1283+5G>A Uncertain significance ★★ same condition
INTS1 c.2977-5C>T Uncertain significance ★★ same condition
INTS1 p.Ala1505Val Uncertain significance ★★ ⚠ same condition
INTS1 p.Ala1854Val Uncertain significance ★★ ⚠ same condition
INTS1 p.Ala2155Val Uncertain significance ★★ ⚠ same condition
INTS1 p.Ala2175Thr Uncertain significance ★★ ⚠ same condition
INTS1 p.Ala4Thr Uncertain significance ★★ ⚠ same condition
INTS1 p.Arg1096Cys Uncertain significance ★★ ⚠ 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-val275ile (accessed [today's date]).

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