Is INTU p.Pro138Ser (c.412C>T) pathogenic?

INTU p.Pro138Ser (c.412C>T) is classified Uncertain significance in INTU (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.2714); Very rare (popmax 0.00136%, nfe); Associated with Inborn genetic diseases.

What condition is associated with INTU p.Pro138Ser (c.412C>T)?

INTU p.Pro138Ser (c.412C>T) is associated with Inborn genetic diseases (ClinVar).

How common is INTU p.Pro138Ser (c.412C>T) in the general population?

INTU p.Pro138Ser (c.412C>T) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about INTU p.Pro138Ser (c.412C>T)?

AlphaMissense predicts likely benign (score 0.2714) — an in-silico prediction, not a clinical call.

INTU p.Pro138Ser

c.412C>T · rs751047941 · VCV2175553

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2714 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2714	likely benign
REVEL	0.326	indeterminate
SaProt	LLR -5.94	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 83 kb · p 0.19 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00136% European (non-Finnish) · 16/1,180,008 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00109% 16/1,461,856 alleles · very rare

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.Pro138Ser
Coding: c.412C>T
MANE Select: NM_015693
dbSNP: rs751047941
Type: single nucleotide variant
Location: chr4:127643786 (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

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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
INTU p.Asp135Gly 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-pro138ser (accessed [today's date]).

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