Is CIT p.Pro1564Gln (c.4691C>A) pathogenic?

CIT p.Pro1564Gln (c.4691C>A) is classified Uncertain significance in CIT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-06). AlphaMissense: ambiguous (0.5124); Ultra-rare (popmax 0.0311%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CIT p.Pro1564Gln (c.4691C>A)?

CIT p.Pro1564Gln (c.4691C>A) is associated with Inborn genetic diseases, microcephaly 17, primary, autosomal recessive (ClinVar).

How common is CIT p.Pro1564Gln (c.4691C>A) in the general population?

CIT p.Pro1564Gln (c.4691C>A) is ultra-rare (popmax 0.0311%, nfe) (gnomAD).

What do computational predictors say about CIT p.Pro1564Gln (c.4691C>A)?

AlphaMissense predicts ambiguous (score 0.5124) — an in-silico prediction, not a clinical call.

CIT p.Pro1564Gln

c.4691C>A · rs564447434 · VCV1030300

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5124 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0311%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5124	ambiguous
REVEL	0.627	indeterminate
SaProt	LLR -7.66	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 32 kb · p 1.5e-18 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1522Q vs ClinVar P1564Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0311% European (non-Finnish) · 366/1,178,016 alleles

Filtering AF 0.0284% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0274%

Overall 0.0238% 384/1,610,078 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0311%	3,219
Remaining individualsnot grpmax-eligible	0.0225%	4,450
African / African-American	0.00401%	24,945
Admixed American	0.00168%	59,432

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.Pro1564Gln
Coding: c.4691C>A
MANE Select: NM_001206999
dbSNP: rs564447434
Type: single nucleotide variant
Location: chr12:119712341 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.75

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

Also linked: microcephaly 17, primary, autosomal recessive

Similar variants

CIT p.Arg1178Ter Pathogenic ★★ same condition
CIT p.Arg220Ter Pathogenic ★★ same condition
CIT c.4168+5G>A Uncertain significance ★★ same condition
CIT p.Ala1144Thr Uncertain significance ★★ ⚠ same condition
CIT p.Ala1527Val Uncertain significance ★★ ⚠ same condition
CIT p.Ala244Val 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-pro1564gln (accessed [today's date]).

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