Is INTU p.Cys653fs (c.1956_1957del) pathogenic?

INTU p.Cys653fs (c.19561957del) is classified Uncertain significance in INTU (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-03). Very rare (popmax 0.00246%, nfe).

How common is INTU p.Cys653fs (c.1956_1957del) in the general population?

INTU p.Cys653fs (c.1956_1957del) is very rare (popmax 0.00246%, nfe) (gnomAD).

INTU p.Cys653fs

c.1956_1957del · rs779599325 · VCV2909380

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.6	GERP 1.7, phastCons 1
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00246% European (non-Finnish) · 29/1,179,942 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00186% 30/1,613,906 alleles · very rare exomes 27/1,461,756 · genomes 3/152,150 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00246%	40,688
African / African-American	0.00134%	74,906

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.Cys653fs
Coding: c.1956_1957del
MANE Select: NM_015693
dbSNP: rs779599325
Type: Deletion
Location: chr4:127706654 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.35 · 4 PDB
Residue 653: a UniProt-annotated variant site (in srtd7/20; in an srtd7/20 patient who also carries variant wdr35 l-311); a UniProt-annotated variant site (in srtd20; loss of subcellular location to cilium basal body, when tested in a heterologous system)

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

Similar variants

INTU p.Lys193fs Pathogenic ★ same type
INTU p.Arg104fs Conflicting classifications of pathogenicity ★ same type
INTU p.Arg399del Uncertain significance ★ same type
INTU p.Asn797fs Uncertain significance ★ same type
INTU p.Asp725fs Uncertain significance ★ same type
INTU p.Leu182fs Uncertain significance ★ same type
INTU p.Leu632fs Uncertain significance ★ same type
INTU c.1450-8del Benign ★ 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-cys653fs (accessed [today's date]).

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