Is CIC p.Arg1605Trp (c.4813C>T) pathogenic?

CIC p.Arg1605Trp (c.4813C>T) is classified Likely benign in CIC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). AlphaMissense: likely benign (0.1331); Very rare (popmax 0.00229%, nfe).

How common is CIC p.Arg1605Trp (c.4813C>T) in the general population?

CIC p.Arg1605Trp (c.4813C>T) is very rare (popmax 0.00229%, nfe) (gnomAD).

What do computational predictors say about CIC p.Arg1605Trp (c.4813C>T)?

AlphaMissense predicts likely benign (score 0.1331) — an in-silico prediction, not a clinical call.

CIC p.Arg1605Trp

c.4813C>T · rs550975604 · VCV3067462

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1331 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.1331	likely benign
REVEL	0.2	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 0.37, phastCons 1
Overall
CADD	24.6	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 R696W vs ClinVar R1605W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00229% European (non-Finnish) · 27/1,178,990 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00226% 33/1,458,880 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00677%	14,778
European (non-Finnish)grpmax	0.00229%	43,666
Admixed American	0.00168%	59,656
Remaining individualsnot grpmax-eligible	0.0016%	62,372
African / African-American	0.00133%	74,982
South Asian	0.0011%	90,802

Ashkenazi Jewish 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.Arg1605Trp
Coding: c.4813C>T
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs550975604
Type: single nucleotide variant
Location: chr19:42290854 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Similar variants

CIC p.Arg1605Gln Likely benign ★★ same residue
CIC c.3179+1G>A Likely pathogenic ★★ same type
CIC c.3179+1G>T Pathogenic ★★ same type
CIC c.5903-2A>G Likely pathogenic ★★ same type
CIC p.Asn1136Ser Likely pathogenic ★★ same type
CIC p.Gln1134Ter Pathogenic ★★ same type
CIC p.Gln1799Ter Likely pathogenic ★★ same type
SLC25A1 c.821+1G>A Pathogenic ★★ 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/cic-p-arg1605trp (accessed [today's date]).

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