Is INTU p.Ser249Pro (c.745T>C) pathogenic?

INTU p.Ser249Pro (c.745T>C) is classified Uncertain significance in INTU (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-08). AlphaMissense: likely pathogenic (0.9529); Absent from gnomAD v4.1.

How common is INTU p.Ser249Pro (c.745T>C) in the general population?

INTU p.Ser249Pro (c.745T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about INTU p.Ser249Pro (c.745T>C)?

AlphaMissense predicts likely pathogenic (score 0.9529) — an in-silico prediction, not a clinical call.

INTU p.Ser249Pro

c.745T>C · VCV4886694

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9529 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9529	likely pathogenic · top 3% in INTU
REVEL	0.291	indeterminate
SaProt	LLR -14.35	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 4.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 83 kb · p 0.19 · regional, not allelic
Overall
CADD	27.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: INTU
Protein: p.Ser249Pro
Coding: c.745T>C
MANE Select: NM_015693
Type: single nucleotide variant
Location: chr4:127656698 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.35 · 4 PDB
Residue 249: the pdz domain

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

Similar variants

INTU p.Ala611Thr Uncertain significance ★★ ⚠ same type
INTU p.Ala804Val Uncertain significance ★★ ⚠ same type
INTU p.Arg119Thr Uncertain significance ★★ ⚠ same type
INTU p.Arg127Cys Uncertain significance ★★ ⚠ same type
INTU p.Arg510Gln Uncertain significance ★★ ⚠ same type
INTU p.Arg510Trp Uncertain significance ★★ ⚠ same type
INTU p.Arg665Cys Uncertain significance ★★ ⚠ same type
INTU p.Arg705Cys 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/intu-p-ser249pro (accessed [today's date]).

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