Is INTU p.Phe90Ser (c.269T>C) pathogenic?

INTU p.Phe90Ser (c.269T>C) is classified Uncertain significance in INTU (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-07). AlphaMissense: likely pathogenic (0.955); Very rare (popmax 0.00805%, nfe); Associated with Inborn genetic diseases.

What condition is associated with INTU p.Phe90Ser (c.269T>C)?

INTU p.Phe90Ser (c.269T>C) is associated with Inborn genetic diseases (ClinVar).

How common is INTU p.Phe90Ser (c.269T>C) in the general population?

INTU p.Phe90Ser (c.269T>C) is very rare (popmax 0.00805%, nfe) (gnomAD).

What do computational predictors say about INTU p.Phe90Ser (c.269T>C)?

AlphaMissense predicts likely pathogenic (score 0.955) — an in-silico prediction, not a clinical call.

INTU p.Phe90Ser

c.269T>C · VCV3710928

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.955 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00805%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.955	likely pathogenic · top 3% in INTU
REVEL	0.354	indeterminate
SaProt	LLR -9.39	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 83 kb · p 0.19 · regional, not allelic
Overall
CADD	25.9	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 0.00805% European (non-Finnish) · 95/1,179,958 alleles

Filtering AF 0.00672% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00624%

Overall 0.00923% 149/1,613,810 alleles · very rare exomes 134/1,461,754 · genomes 15/152,056 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0625%	1,599
Remaining individualsnot grpmax-eligible	0.0208%	4,808
European (non-Finnish)grpmax	0.00805%	12,421
African / African-American	0.00133%	74,936

Finnish 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: INTU
Protein: p.Phe90Ser
Coding: c.269T>C
MANE Select: NM_015693
Type: single nucleotide variant
Location: chr4:127643643 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.35 · 4 PDB

Full INTU 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

INTU p.Phe90= Likely benign ★ same residue
INTU p.Ala611Thr Uncertain significance ★★ ⚠ same condition
INTU p.Ala804Val Uncertain significance ★★ ⚠ same condition
INTU p.Arg119Thr Uncertain significance ★★ ⚠ same condition
INTU p.Arg127Cys Uncertain significance ★★ ⚠ same condition
INTU p.Arg510Trp Uncertain significance ★★ ⚠ same condition
INTU p.Arg665Cys Uncertain significance ★★ ⚠ same condition
INTU p.Arg705Cys 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/intu-p-phe90ser (accessed [today's date]).

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