Is CIC p.Pro1325Ser (c.3973C>T) pathogenic?

CIC p.Pro1325Ser (c.3973C>T) is classified Uncertain significance in CIC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-19). AlphaMissense: likely benign (0.0879); Very rare (popmax 0.0011%, sas); Associated with CIC-related disorder.

What condition is associated with CIC p.Pro1325Ser (c.3973C>T)?

CIC p.Pro1325Ser (c.3973C>T) is associated with CIC-related disorder (ClinVar).

How common is CIC p.Pro1325Ser (c.3973C>T) in the general population?

CIC p.Pro1325Ser (c.3973C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CIC p.Pro1325Ser (c.3973C>T)?

AlphaMissense predicts likely benign (score 0.0879) — an in-silico prediction, not a clinical call.

CIC p.Pro1325Ser

c.3973C>T · rs770404685 · VCV2635553

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0879 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

CIC-related disorder

Computational evidence

Protein change
AlphaMissense	0.0879	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.18, phastCons 1
Overall
CADD	22.4	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 is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P416S vs ClinVar P1325S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,090 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,744 alleles · very rare exomes 2/1,461,528 · genomes 1/152,216 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,090
European (non-Finnish)	0.000169%	590,016

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.Pro1325Ser
Coding: c.3973C>T
MANE Select: NM_001386298
dbSNP: rs770404685
Type: single nucleotide variant
Location: chr19:42289292 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Disease context

CIC-related disorder

Similar variants

CIC p.Pro1325Leu Uncertain significance ★ ⚠ same residue
CIC p.Asn1136Ser Likely pathogenic ★★ same condition
SLC25A1 p.Ala274Val Pathogenic/Likely pathogenic ★★ same condition
SLC25A1 p.Glu174Ter Pathogenic/Likely pathogenic ★★ same condition
CIC p.Arg2114Trp Uncertain significance ★★ ⚠ same condition
CIC p.Arg800His Uncertain significance ★★ same condition
CIC p.Gly17Val Uncertain significance ★★ same condition
CIC p.Val989Ala 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-pro1325ser (accessed [today's date]).

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