Is INTS1 p.Gln1448Arg (c.4343A>G) pathogenic?

INTS1 p.Gln1448Arg (c.4343A>G) is classified Conflicting classifications of pathogenicity in INTS1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.0769); Rare (popmax 0.152%, nfe).

How common is INTS1 p.Gln1448Arg (c.4343A>G) in the general population?

INTS1 p.Gln1448Arg (c.4343A>G) is rare (popmax 0.152%, nfe) (gnomAD).

What do computational predictors say about INTS1 p.Gln1448Arg (c.4343A>G)?

AlphaMissense predicts likely benign (score 0.0769) — an in-silico prediction, not a clinical call.

INTS1 p.Gln1448Arg

c.4343A>G · rs185292877 · VCV641028

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0769 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.152%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0769	likely benign
REVEL	0.389	indeterminate
SaProt	LLR -3.39	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 6.1	GERP 1.1, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	23.0	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 0.152% European (non-Finnish) · 1,784/1,176,832 alleles

Filtering AF 0.146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.143%

Overall 0.119% 1,906/1,608,260 alleles · rare exomes 1,752/1,455,902 · genomes 154/152,358 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	2.63%	38
European (non-Finnish)grpmax	0.152%	660
Remaining individualsnot grpmax-eligible	0.0836%	1,197
Admixed American	0.0401%	2,494
African / African-American	0.0253%	3,945
Middle Eastern	0.0166%	6,038
Finnishnot grpmax-eligible	0.0032%	31,205

Amish 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.Gln1448Arg
Coding: c.4343A>G
MANE Select: NM_001080453
dbSNP: rs185292877
Type: single nucleotide variant
Location: chr7:1478872 (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

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-gln1448arg (accessed [today's date]).

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