Is INTS1 p.Pro749Ser (c.2245C>T) pathogenic?

INTS1 p.Pro749Ser (c.2245C>T) is classified Uncertain significance in INTS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-26). AlphaMissense: likely pathogenic (0.8154); Very rare (popmax 0.00913%, eas); Associated with Inborn genetic diseases.

What condition is associated with INTS1 p.Pro749Ser (c.2245C>T)?

INTS1 p.Pro749Ser (c.2245C>T) is associated with Inborn genetic diseases (ClinVar).

How common is INTS1 p.Pro749Ser (c.2245C>T) in the general population?

INTS1 p.Pro749Ser (c.2245C>T) is very rare (popmax 0.00913%, eas) (gnomAD).

What do computational predictors say about INTS1 p.Pro749Ser (c.2245C>T)?

AlphaMissense predicts likely pathogenic (score 0.8154) — an in-silico prediction, not a clinical call.

INTS1 p.Pro749Ser

c.2245C>T · VCV3286203

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8154 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00913%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8154	likely pathogenic
REVEL	0.603	indeterminate
SaProt	LLR -10.26	damaging
⇒ AlphaMissense and SaProt both call this damaging; 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 0.96	unconstrained · MANE · 21 kb · p 0.12 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00913% East Asian · 4/43,828 alleles

Filtering AF 0.00303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00107% 17/1,587,006 alleles · very rare exomes 15/1,434,736 · genomes 2/152,270 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00913%	10,957
Remaining individualsnot grpmax-eligible	0.00326%	30,680
European (non-Finnish)	0.000944%	105,960

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.Pro749Ser
Coding: c.2245C>T
MANE Select: NM_001080453
Type: single nucleotide variant
Location: chr7:1489603 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 749: a turn

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-pro749ser (accessed [today's date]).

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