Is CIT p.Phe375fs (c.1122dup) pathogenic?

CIT p.Phe375fs (c.1122dup) is classified Likely pathogenic in CIT (ClinVar, Single submitter, 1 submitter; last evaluated 2017-01-27). Very rare (popmax 8.61e-05%, nfe).

How common is CIT p.Phe375fs (c.1122dup) in the general population?

CIT p.Phe375fs (c.1122dup) is very rare (popmax 8.61e-05%, nfe) (gnomAD).

CIT p.Phe375fs

c.1122dup · rs1057520205 · VCV377365

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.61e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 10 of 48
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Overall
CADD	34.0	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 8.61e-05% European (non-Finnish) · 1/1,161,064 alleles

Overall 6.38e-05% 1/1,566,690 alleles · very rare exomes 0/1,414,570 · genomes 1/152,120 · 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: CIT
Protein: p.Phe375fs
Coding: c.1122dup
MANE Select: NM_001206999
dbSNP: rs1057520205
Type: Duplication
Location: chr12:119803378 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.75
Residue 375: the agc-kinase c-terminal domain

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

Similar variants

CIT p.Phe375= Uncertain significance ★ same residue
CIT p.Glu143Ter Pathogenic ★ same type
CIT c.1546-213dup Benign ★ same type
CIT c.1942-121dup Benign ★ same type
CIT c.2304+198dup Likely benign ★ same type
CIT c.2706+206dup Likely benign ★ same type
CIT c.2706+238dup Benign ★ same type
CIT c.415-113_415-110dup Likely 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/cit-p-phe375fs (accessed [today's date]).

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