Is CIC p.Thr193Ser (c.577A>T) pathogenic?

CIC p.Thr193Ser (c.577A>T) is classified Conflicting classifications of pathogenicity in CIC (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-05-01). Rare (popmax 0.52%, nfe); Associated with intellectual developmental disorder, autosomal dominant 45.

What condition is associated with CIC p.Thr193Ser (c.577A>T)?

CIC p.Thr193Ser (c.577A>T) is associated with intellectual developmental disorder, autosomal dominant 45 (ClinVar).

How common is CIC p.Thr193Ser (c.577A>T) in the general population?

CIC p.Thr193Ser (c.577A>T) is rare (popmax 0.52%, nfe) (gnomAD).

CIC p.Thr193Ser

c.577A>T · rs547565552 · VCV983341

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.52%, nfe)

Conditions

intellectual developmental disorder, autosomal dominant 45

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.6	GERP -2.1
Overall
CADD	3.441	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.52% European (non-Finnish) · 1,174/225,964 alleles

Filtering AF 0.495% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.485%

Overall 0.347% 1,383/398,484 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.86%	54
European (non-Finnish)grpmax	0.52%	192
Remaining individualsnot grpmax-eligible	0.292%	342
Finnishnot grpmax-eligible	0.191%	524
Admixed American	0.101%	989
Ashkenazi Jewishnot grpmax-eligible	0.0945%	1,058
African / African-American	0.0862%	1,160
South Asian	0.0127%	7,860

Amish 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: CIC
Protein: p.Thr193Ser
Coding: c.577A>T
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs547565552
Type: single nucleotide variant
Location: chr19:42272360 (GRCh38)
Structure: AlphaFold pLDDT 75.09
Residue 193: a UniProt-annotated variant site (in d2l2ad; reduced rates of citrate transport)

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

Disease context

intellectual developmental disorder, autosomal dominant 45 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SLC25A1 p.Ser193Leu Likely pathogenic ★★ same residue
CIC c.3179+1G>T Pathogenic ★★ same condition
CIC c.5903-2A>G Likely pathogenic ★★ same condition
CIC p.Asn1136Ser Likely pathogenic ★★ same condition
CIC p.Gln1134Ter Pathogenic ★★ same condition
CIC p.Gln1799Ter Likely pathogenic ★★ same condition
CIC p.Ala1761Val Uncertain significance ★★ ⚠ same condition
CIC p.Ala2064Thr 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-thr193ser (accessed [today's date]).

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