Is CIT p.Pro374Ala (c.1120C>G) pathogenic?

CIT p.Pro374Ala (c.1120C>G) is classified Uncertain significance in CIT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: ambiguous (0.3921); Ultra-rare (popmax 0.0519%, eas); Associated with Inborn genetic diseases.

What condition is associated with CIT p.Pro374Ala (c.1120C>G)?

CIT p.Pro374Ala (c.1120C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CIT p.Pro374Ala (c.1120C>G) in the general population?

CIT p.Pro374Ala (c.1120C>G) is ultra-rare (popmax 0.0519%, eas) (gnomAD).

What do computational predictors say about CIT p.Pro374Ala (c.1120C>G)?

AlphaMissense predicts ambiguous (score 0.3921) — an in-silico prediction, not a clinical call.

CIT p.Pro374Ala

c.1120C>G · VCV4003127

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3921 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0519%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3921	ambiguous
REVEL	0.425	indeterminate
SaProt	LLR -9.97	tolerated
Splicing
SpliceAI	Δ0.29	acceptor gain, 8 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 91 kb · p 0.38 · regional, not allelic
Overall
CADD	27.8	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 0.0519% East Asian · 22/42,386 alleles

Filtering AF 0.0351% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0296%

Overall 0.00186% 29/1,558,912 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0519%	1,927
African / African-American	0.00843%	11,859
South Asian	0.00119%	84,052

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.Pro374Ala
Coding: c.1120C>G
MANE Select: NM_001206999
Type: single nucleotide variant
Location: chr12:119803381 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CIT p.Pro374Thr Uncertain significance ★ ⚠ same residue
CIT p.Pro374Arg Uncertain significance ★★ ⚠ same residue
CIT p.Pro374His Uncertain significance ★★ ⚠ same residue
CIT p.Arg1178Ter Pathogenic ★★ same condition
CIT c.4168+5G>A Uncertain significance ★★ same condition
CIT p.Ala1527Val Uncertain significance ★★ ⚠ same condition
CIT p.Ala495Ser Uncertain significance ★★ ⚠ same condition
CIT p.Ala8Val 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-pro374ala (accessed [today's date]).

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