Is INTS1 p.Ala1847Val (c.5540C>T) pathogenic?

INTS1 p.Ala1847Val (c.5540C>T) is classified Conflicting classifications of pathogenicity in INTS1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-06-19). AlphaMissense: likely benign (0.2549); Rare (popmax 0.535%, afr).

How common is INTS1 p.Ala1847Val (c.5540C>T) in the general population?

INTS1 p.Ala1847Val (c.5540C>T) is rare (popmax 0.535%, afr) (gnomAD).

What do computational predictors say about INTS1 p.Ala1847Val (c.5540C>T)?

AlphaMissense predicts likely benign (score 0.2549) — an in-silico prediction, not a clinical call.

INTS1 p.Ala1847Val

c.5540C>T · rs201606213 · VCV726061

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2549 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.535%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2549	likely benign
REVEL	0.398	indeterminate
SaProt	LLR -7.03	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	27.0	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 0.535% African / African-American · 399/74,552 alleles

Filtering AF 0.492% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.475%

Overall 0.034% 540/1,589,464 alleles · rare exomes 300/1,437,152 · genomes 240/152,312 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.535%	187
Admixed American	0.07%	1,428
Remaining individualsnot grpmax-eligible	0.0537%	1,863
Middle Eastern	0.0445%	2,245
European (non-Finnish)	0.00513%	19,507
East Asian	0.00458%	21,852
South Asian	0.00345%	28,989
Finnishnot grpmax-eligible	0.00165%	60,710

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.Ala1847Val
Coding: c.5540C>T
MANE Select: NM_001080453
dbSNP: rs201606213
Type: single nucleotide variant
Location: chr7:1474801 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 1847: an α-helix; a UniProt-annotated variant site (in ndcagf; decreased protein abundance)

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-ala1847val (accessed [today's date]).

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