Is CIT p.Pro374Arg (c.1121C>G) pathogenic?

CIT p.Pro374Arg (c.1121C>G) is classified Uncertain significance in CIT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-14). AlphaMissense: likely pathogenic (0.7981); Rare (popmax 0.144%, mid); Associated with microcephaly 17, primary, autosomal recessive.

What condition is associated with CIT p.Pro374Arg (c.1121C>G)?

CIT p.Pro374Arg (c.1121C>G) is associated with microcephaly 17, primary, autosomal recessive (ClinVar).

How common is CIT p.Pro374Arg (c.1121C>G) in the general population?

CIT p.Pro374Arg (c.1121C>G) is rare (popmax 0.144%, mid) (gnomAD).

What do computational predictors say about CIT p.Pro374Arg (c.1121C>G)?

AlphaMissense predicts likely pathogenic (score 0.7981) — an in-silico prediction, not a clinical call.

CIT p.Pro374Arg

c.1121C>G · rs200052993 · VCV1337123

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7981 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.144%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microcephaly 17, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.7981	likely pathogenic
REVEL	0.757	pathogenic-leaning
SaProt	LLR -12.99	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.24	acceptor gain, 9 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 9.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 91 kb · p 0.38 · regional, not allelic
Overall
CADD	27.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.144% Middle Eastern · 8/5,566 alleles

Filtering AF 0.0715% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0522%

Overall 0.00676% 106/1,566,938 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.144%	696
Admixed American	0.008%	12,498
European (non-Finnish)	0.00706%	14,160
Remaining individualsnot grpmax-eligible	0.00665%	15,048
African / African-American	0.00558%	17,932
East Asian	0.00469%	21,301
Finnishnot grpmax-eligible	0.00159%	63,034
South Asian	0.00118%	84,874

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.Pro374Arg
Coding: c.1121C>G
MANE Select: NM_001206999
dbSNP: rs200052993
Type: single nucleotide variant
Location: chr12:119803380 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.75
Residue 374: the agc-kinase c-terminal 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.Pro374His Uncertain significance ★★ ⚠ same residue
CIT p.Pro374Ala Uncertain significance ★ same residue
CIT p.Pro374Thr Uncertain significance ★ ⚠ same residue
CIT p.Arg220Ter Pathogenic ★★ same condition
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

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-pro374arg (accessed [today's date]).

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