Is CIT p.Arg220Ter (c.658C>T) pathogenic?

CIT p.Arg220Ter (c.658C>T) is classified Pathogenic in CIT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-27). Ultra-rare (popmax 0.0166%, mid); Associated with microcephaly 17, primary, autosomal recessive.

What condition is associated with CIT p.Arg220Ter (c.658C>T)?

CIT p.Arg220Ter (c.658C>T) is associated with microcephaly 17, primary, autosomal recessive (ClinVar).

How common is CIT p.Arg220Ter (c.658C>T) in the general population?

CIT p.Arg220Ter (c.658C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

CIT p.Arg220Ter

c.658C>T · rs202076791 · VCV871735

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Conditions

microcephaly 17, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 6 of 48
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP -0.014, phastCons 1
Overall
CADD	40.0	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 0.0166% Middle Eastern · 1/6,040 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00243% 39/1,606,316 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0177%	5,653
Middle Easterngrpmax	0.0166%	6,040
African / African-American	0.00269%	37,242
European (non-Finnish)	0.00212%	47,115

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg220Ter
Coding: c.658C>T
MANE Select: NM_001206999
dbSNP: rs202076791
Type: single nucleotide variant
Location: chr12:119834087 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.75
Residue 220: the protein kinase domain

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

Disease context

microcephaly 17, primary, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CIT p.Ala1144Thr Uncertain significance ★★ ⚠ same condition
CIT p.Ala244Val Uncertain significance ★★ ⚠ same condition
CIT p.Arg1633Cys Uncertain significance ★★ ⚠ same condition
CIT p.Arg23Trp Uncertain significance ★★ ⚠ same condition
CIT p.Arg696Cys Uncertain significance ★★ same condition
CIT p.Asn1301Ser Uncertain significance ★★ ⚠ same condition
CIT p.Asn786Ser Uncertain significance ★★ ⚠ same condition
CIT p.Gln1645Lys 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/cit-p-arg220ter (accessed [today's date]).

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