Is INTU p.Ser334Phe (c.1001C>T) pathogenic?

INTU p.Ser334Phe (c.1001C>T) is classified Uncertain significance in INTU (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-13). AlphaMissense: ambiguous (0.5014); Ultra-rare (popmax 0.0347%, amr).

How common is INTU p.Ser334Phe (c.1001C>T) in the general population?

INTU p.Ser334Phe (c.1001C>T) is ultra-rare (popmax 0.0347%, amr) (gnomAD).

What do computational predictors say about INTU p.Ser334Phe (c.1001C>T)?

AlphaMissense predicts ambiguous (score 0.5014) — an in-silico prediction, not a clinical call.

INTU p.Ser334Phe

c.1001C>T · rs192164921 · VCV2190610

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5014 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, amr)

Computational evidence

Protein change
AlphaMissense	0.5014	ambiguous
REVEL	0.411	indeterminate
SaProt	LLR -6.72	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 83 kb · p 0.19 · regional, not allelic
Overall
CADD	26.8	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 0.0347% Admixed American · 19/54,820 alleles

Filtering AF 0.0227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.00124% 19/1,529,348 alleles · ultra-rare exomes 18/1,377,546 · genomes 1/151,802 · 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.Ser334Phe
Coding: c.1001C>T
MANE Select: NM_015693
dbSNP: rs192164921
Type: single nucleotide variant
Location: chr4:127669064 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.35 · 4 PDB
Residue 334: a UniProt-annotated variant site (in srtd7/20; in an srtd7/20 patient who also carries variant wdr35 l-311)

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-ser334phe (accessed [today's date]).

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