Is CIT p.Arg1595Ser (c.4783C>A) pathogenic?

CIT p.Arg1595Ser (c.4783C>A) is classified Uncertain significance in CIT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-27). AlphaMissense: likely pathogenic (0.8673); Very rare (popmax 0.000424%, nfe).

How common is CIT p.Arg1595Ser (c.4783C>A) in the general population?

CIT p.Arg1595Ser (c.4783C>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about CIT p.Arg1595Ser (c.4783C>A)?

AlphaMissense predicts likely pathogenic (score 0.8673) — an in-silico prediction, not a clinical call.

CIT p.Arg1595Ser

c.4783C>A · rs1165615595 · VCV1971722

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8673 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8673	likely pathogenic
REVEL	0.504	indeterminate
SaProt	LLR -7.81	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 32 kb · p 1.5e-18 · regional, not allelic
Overall
CADD	26.8	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 R1553S vs ClinVar R1595S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,986 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,994 alleles · very rare

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.Arg1595Ser
Coding: c.4783C>A
MANE Select: NM_001206999
dbSNP: rs1165615595
Type: single nucleotide variant
Location: chr12:119712249 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.75
Residue 1595: the cnh domain

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

Similar variants

CIT p.Arg1595Cys 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-arg1595ser (accessed [today's date]).

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