Is INTU p.Arg89Ser (c.267G>C) pathogenic?

INTU p.Arg89Ser (c.267G>C) is classified Uncertain significance in INTU (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-13). AlphaMissense: likely pathogenic (0.6302); Very rare (popmax 0.00133%, afr).

How common is INTU p.Arg89Ser (c.267G>C) in the general population?

INTU p.Arg89Ser (c.267G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about INTU p.Arg89Ser (c.267G>C)?

AlphaMissense predicts likely pathogenic (score 0.6302) — an in-silico prediction, not a clinical call.

INTU p.Arg89Ser

c.267G>C · rs1727431574 · VCV1393254

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6302 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6302	likely pathogenic
REVEL	0.308	indeterminate
SaProt	LLR -5.70	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 0.41	GERP -0.11, phastCons 0.98
Regional constraint	o/e 0.96	unconstrained · MANE · 83 kb · p 0.19 · regional, not allelic
Overall
CADD	21.3	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 0.00133% African / African-American · 1/74,912 alleles

Overall 6.2e-05% 1/1,613,742 alleles · very rare exomes 1/1,461,726 · genomes 0/152,016 · joint denominator

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.Arg89Ser
Coding: c.267G>C
MANE Select: NM_015693
dbSNP: rs1727431574
Type: single nucleotide variant
Location: chr4:127643641 (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

Similar variants

INTU p.Arg89Thr Uncertain significance ★ same residue
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

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-arg89ser (accessed [today's date]).

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