Is INTS1 p.Ile541Val (c.1621A>G) pathogenic?

INTS1 p.Ile541Val (c.1621A>G) is classified Uncertain significance in INTS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-21). AlphaMissense: likely benign (0.0582); Ultra-rare (popmax 0.0334%, eas); Associated with Inborn genetic diseases.

What condition is associated with INTS1 p.Ile541Val (c.1621A>G)?

INTS1 p.Ile541Val (c.1621A>G) is associated with Inborn genetic diseases (ClinVar).

How common is INTS1 p.Ile541Val (c.1621A>G) in the general population?

INTS1 p.Ile541Val (c.1621A>G) is ultra-rare (popmax 0.0334%, eas) (gnomAD).

What do computational predictors say about INTS1 p.Ile541Val (c.1621A>G)?

AlphaMissense predicts likely benign (score 0.0582) — an in-silico prediction, not a clinical call.

INTS1 p.Ile541Val

c.1621A>G · rs201219032 · VCV2209929

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0582 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0582	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -4.85	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 0.33	GERP -2.3, phastCons 0.075
Regional constraint	o/e 0.96	unconstrained · MANE · 21 kb · p 0.12 · regional, not allelic
Overall
CADD	9.708	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 0.0334% East Asian · 15/44,848 alleles

Filtering AF 0.0206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0166%

Overall 0.00124% 20/1,613,716 alleles · ultra-rare exomes 16/1,461,424 · genomes 4/152,292 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0334%	2,990
Middle Eastern	0.0165%	6,058
Admixed American	0.00167%	60,016
European (non-Finnish)	0.000254%	393,263

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.Ile541Val
Coding: c.1621A>G
MANE Select: NM_001080453
dbSNP: rs201219032
Type: single nucleotide variant
Location: chr7:1496246 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 541: an α-helix

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-ile541val (accessed [today's date]).

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