Is CIT p.Pro1377Leu (c.4130C>T) pathogenic?

CIT p.Pro1377Leu (c.4130C>T) is classified Uncertain significance in CIT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-03). AlphaMissense: likely benign (0.2087); Very rare (popmax 0.00119%, nfe); Associated with microcephaly 17, primary, autosomal recessive.

What condition is associated with CIT p.Pro1377Leu (c.4130C>T)?

CIT p.Pro1377Leu (c.4130C>T) is associated with microcephaly 17, primary, autosomal recessive (ClinVar).

How common is CIT p.Pro1377Leu (c.4130C>T) in the general population?

CIT p.Pro1377Leu (c.4130C>T) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about CIT p.Pro1377Leu (c.4130C>T)?

AlphaMissense predicts likely benign (score 0.2087) — an in-silico prediction, not a clinical call.

CIT p.Pro1377Leu

c.4130C>T · rs779515686 · VCV560261

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2087 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microcephaly 17, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.2087	likely benign
REVEL	0.171	moderately benign-leaning
SaProt	LLR -6.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 32 kb · p 1.5e-18 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

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

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1335L vs ClinVar P1377L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00119% European (non-Finnish) · 14/1,179,702 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00205% 33/1,613,466 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0608%	1,644
Remaining individualsnot grpmax-eligible	0.0016%	62,458
European (non-Finnish)grpmax	0.00119%	84,264

Ashkenazi Jewish 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.Pro1377Leu
Coding: c.4130C>T
MANE Select: NM_001206999
dbSNP: rs779515686
Type: single nucleotide variant
Location: chr12:119718283 (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

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

Similar variants

CIT p.Pro1377= Likely benign 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
CIT p.Arg696Cys Uncertain significance ★★ same condition
CIT p.Asn1301Ser 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-pro1377leu (accessed [today's date]).

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