Is CIC p.Ser1953Pro (c.5857T>C) pathogenic?

CIC p.Ser1953Pro (c.5857T>C) is classified Likely benign in CIC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). AlphaMissense: ambiguous (0.4169); Rare (popmax 0.105%, amr); Associated with Inborn genetic diseases.

What condition is associated with CIC p.Ser1953Pro (c.5857T>C)?

CIC p.Ser1953Pro (c.5857T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CIC p.Ser1953Pro (c.5857T>C) in the general population?

CIC p.Ser1953Pro (c.5857T>C) is rare (popmax 0.105%, amr) (gnomAD).

What do computational predictors say about CIC p.Ser1953Pro (c.5857T>C)?

AlphaMissense predicts ambiguous (score 0.4169) — an in-silico prediction, not a clinical call.

CIC p.Ser1953Pro

c.5857T>C · rs555135145 · VCV735244

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4169 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.105%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4169	ambiguous
REVEL	0.356	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 1.7, phastCons 1
Overall
CADD	24.3	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 S1044P vs ClinVar S1953P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.105% Admixed American · 63/59,954 alleles

Filtering AF 0.0842% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0767%

Overall 0.0113% 182/1,610,978 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.105%	952
Remaining individualsnot grpmax-eligible	0.0385%	2,598
European (non-Finnish)	0.00764%	13,096
African / African-American	0.00534%	18,724
South Asian	0.0011%	91,040

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: CIC
Protein: p.Ser1953Pro
Coding: c.5857T>C
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs555135145
Type: single nucleotide variant
Location: chr19:42292421 (GRCh38)
Structure: AlphaFold pLDDT 75.09

Full CIC 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

CIC c.2795-2056C>T Uncertain significance ★★ ⚠ same condition
CIC p.Ala1228Val Uncertain significance ★★ ⚠ same condition
CIC p.Ala1445Gly Uncertain significance ★★ ⚠ same condition
CIC p.Ala1750Val Uncertain significance ★★ ⚠ same condition
CIC p.Ala1975Gly Uncertain significance ★★ ⚠ same condition
CIC p.Ala2463Thr Uncertain significance ★★ ⚠ same condition
CIC p.Arg1205Trp Uncertain significance ★★ ⚠ same condition
CIC p.Arg1481Gln 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/cic-p-ser1953pro (accessed [today's date]).

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