Is CIC p.Arg2195His (c.6584G>A) pathogenic?

CIC p.Arg2195His (c.6584G>A) is classified Uncertain significance in CIC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-19). AlphaMissense: likely benign (0.1189); Ultra-rare (popmax 0.0253%, sas); Associated with Dias-Logan syndrome.

What condition is associated with CIC p.Arg2195His (c.6584G>A)?

CIC p.Arg2195His (c.6584G>A) is associated with Dias-Logan syndrome, intellectual developmental disorder, autosomal dominant 45 (ClinVar).

How common is CIC p.Arg2195His (c.6584G>A) in the general population?

CIC p.Arg2195His (c.6584G>A) is ultra-rare (popmax 0.0253%, sas) (gnomAD).

What do computational predictors say about CIC p.Arg2195His (c.6584G>A)?

AlphaMissense predicts likely benign (score 0.1189) — an in-silico prediction, not a clinical call.

CIC p.Arg2195His

Q: How is Hereditary persistence of fetal hemoglobin-intellectual disability syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.6584G>A · rs759057387 · VCV2499468

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1189 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Dias-Logan syndrome

Computational evidence

Protein change
AlphaMissense	0.1189	likely benign
REVEL	0.133	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	Δ0.57	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 8.4	GERP 1.6, phastCons 1
Overall
CADD	34.0	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 R1286H vs ClinVar R2195H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0253% South Asian · 23/91,034 alleles

Filtering AF 0.0172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0146%

Overall 0.00403% 65/1,613,018 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0253%	3,958
Remaining individualsnot grpmax-eligible	0.00801%	12,490
European (non-Finnish)	0.00297%	33,711
East Asian	0.00223%	44,894
Admixed American	0.00167%	59,950

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.Arg2195His
Coding: c.6584G>A
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs759057387
Type: single nucleotide variant
Location: chr19:42293653 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Disease context

Dias-Logan syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual developmental disorder, autosomal dominant 45

For Hereditary persistence of fetal hemoglobin-intellectual disability syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

CIC p.Arg2195Pro Uncertain significance ★ ⚠ 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-arg2195his (accessed [today's date]).

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