Is CIT p.Pro358Ala (c.1072C>G) pathogenic?

CIT p.Pro358Ala (c.1072C>G) is classified Likely benign in CIT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-09). AlphaMissense: likely benign (0.0919); Rare (popmax 0.102%, amr).

How common is CIT p.Pro358Ala (c.1072C>G) in the general population?

CIT p.Pro358Ala (c.1072C>G) is rare (popmax 0.102%, amr) (gnomAD).

What do computational predictors say about CIT p.Pro358Ala (c.1072C>G)?

AlphaMissense predicts likely benign (score 0.0919) — an in-silico prediction, not a clinical call.

CIT p.Pro358Ala

c.1072C>G · rs199836387 · VCV2014560

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0919 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.102%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0919	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -9.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.5	GERP -0.76, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 91 kb · p 0.38 · regional, not allelic
Overall
CADD	19.96	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 0.102% Admixed American · 61/60,008 alleles

Filtering AF 0.0811% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0738%

Overall 0.0039% 63/1,614,086 alleles · rare exomes 55/1,461,840 · genomes 8/152,246 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.102%	984
Remaining individualsnot grpmax-eligible	0.0032%	31,254

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.Pro358Ala
Coding: c.1072C>G
MANE Select: NM_001206999
dbSNP: rs199836387
Type: single nucleotide variant
Location: chr12:119822859 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.75
Residue 358: the protein kinase domain

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

Similar variants

CIT p.Pro358His Uncertain significance ★ ⚠ same residue
CIT p.Arg1178Ter Pathogenic ★★ same type
CIT p.Arg220Ter Pathogenic ★★ same type
CIT c.4168+5G>A Uncertain significance ★★ same type
CIT p.Ala1144Thr Uncertain significance ★★ ⚠ same type
CIT p.Ala1466Asp Uncertain significance ★★ ⚠ same type
CIT p.Ala1527Val Uncertain significance ★★ ⚠ same type
CIT p.Ala244Val Uncertain significance ★★ ⚠ 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-pro358ala (accessed [today's date]).

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