Is INTS1 p.Phe1990Leu (c.5970C>G) pathogenic?

INTS1 p.Phe1990Leu (c.5970C>G) is classified Conflicting classifications of pathogenicity in INTS1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-16). AlphaMissense: likely pathogenic (0.607); Rare (popmax 0.5%, eas); Associated with neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies.

What condition is associated with INTS1 p.Phe1990Leu (c.5970C>G)?

INTS1 p.Phe1990Leu (c.5970C>G) is associated with neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies (ClinVar).

How common is INTS1 p.Phe1990Leu (c.5970C>G) in the general population?

INTS1 p.Phe1990Leu (c.5970C>G) is rare (popmax 0.5%, eas) (gnomAD).

What do computational predictors say about INTS1 p.Phe1990Leu (c.5970C>G)?

AlphaMissense predicts likely pathogenic (score 0.607) — an in-silico prediction, not a clinical call.

INTS1 p.Phe1990Leu

c.5970C>G · rs138397380 · VCV1699198

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.607 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.5%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies

Computational evidence

Protein change
AlphaMissense	0.607	likely pathogenic
REVEL	0.03	moderately benign-leaning
SaProt	LLR -3.62	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.6	GERP -3.1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	0.255	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 0.5% East Asian · 224/44,842 alleles

Filtering AF 0.446% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.425%

Overall 0.0188% 303/1,610,854 alleles · rare exomes 277/1,458,526 · genomes 26/152,328 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.5%	200
South Asian	0.0539%	1,857
Middle Eastern	0.0165%	6,054
Remaining individualsnot grpmax-eligible	0.016%	6,237
Finnishnot grpmax-eligible	0.00319%	31,380
European (non-Finnish)	0.00144%	69,322

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.Phe1990Leu
Coding: c.5970C>G
MANE Select: NM_001080453
dbSNP: rs138397380
Type: single nucleotide variant
Location: chr7:1473172 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 1990: an α-helix; a UniProt-annotated variant site (in ndcagf; decreased protein abundance); a UniProt-annotated variant site (in ndcagf)

Full INTS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

INTS1 p.Phe1990= Likely benign ★ same residue
INTS1 c.3430-2A>C Likely pathogenic ★★ same condition
INTS1 p.Arg101Ter Likely pathogenic ★★ same condition
INTS1 c.1283+5G>A Uncertain significance ★★ same condition
INTS1 c.2977-5C>T Uncertain significance ★★ same condition
INTS1 p.Ala745Thr Uncertain significance ★★ ⚠ same condition
INTS1 p.Arg1130Cys Uncertain significance ★★ ⚠ same condition
INTS1 p.Arg1685Gln 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-phe1990leu (accessed [today's date]).

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