Is INTS1 p.Val1255Met (c.3763G>A) pathogenic?

INTS1 p.Val1255Met (c.3763G>A) is classified Uncertain significance in INTS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-31). AlphaMissense: likely pathogenic (0.7905); Very rare (popmax 0.00549%, sas); Associated with Inborn genetic diseases.

What condition is associated with INTS1 p.Val1255Met (c.3763G>A)?

INTS1 p.Val1255Met (c.3763G>A) is associated with Inborn genetic diseases (ClinVar).

How common is INTS1 p.Val1255Met (c.3763G>A) in the general population?

INTS1 p.Val1255Met (c.3763G>A) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about INTS1 p.Val1255Met (c.3763G>A)?

AlphaMissense predicts likely pathogenic (score 0.7905) — an in-silico prediction, not a clinical call.

INTS1 p.Val1255Met

c.3763G>A · VCV3286197

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7905 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7905	likely pathogenic
REVEL	0.498	indeterminate
SaProt	LLR -9.23	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	26.9	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 0.00549% South Asian · 5/91,024 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000808% 13/1,609,390 alleles · very rare exomes 11/1,457,430 · genomes 2/151,960 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,205
Remaining individualsnot grpmax-eligible	0.00161%	62,210
African / African-American	0.00134%	74,764
European (non-Finnish)	0.000509%	196,333

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.Val1255Met
Coding: c.3763G>A
MANE Select: NM_001080453
Type: single nucleotide variant
Location: chr7:1481429 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 1255: 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 p.Val1255= Likely benign ★★ same residue
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

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-val1255met (accessed [today's date]).

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