Is CIC p.Pro1651Ser (c.4951C>T) pathogenic?

CIC p.Pro1651Ser (c.4951C>T) is classified Likely benign in CIC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.1142); Rare (popmax 0.313%, mid); Associated with Inborn genetic diseases.

What condition is associated with CIC p.Pro1651Ser (c.4951C>T)?

CIC p.Pro1651Ser (c.4951C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CIC p.Pro1651Ser (c.4951C>T) in the general population?

CIC p.Pro1651Ser (c.4951C>T) is rare (popmax 0.313%, mid) (gnomAD).

What do computational predictors say about CIC p.Pro1651Ser (c.4951C>T)?

AlphaMissense predicts likely benign (score 0.1142) — an in-silico prediction, not a clinical call.

CIC p.Pro1651Ser

c.4951C>T · rs201439084 · VCV2393770

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1142 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.313%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1142	likely benign
REVEL	0.085	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 4.1	GERP 1.4, phastCons 1
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P742S vs ClinVar P1651S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.313% Middle Eastern · 19/6,062 alleles

Filtering AF 0.205% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.171%

Overall 0.0294% 474/1,613,828 alleles · rare exomes 394/1,461,520 · genomes 80/152,308 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.313%	319
Admixed American	0.193%	517
Remaining individualsnot grpmax-eligible	0.0736%	1,359
European (non-Finnish)	0.0242%	4,126
African / African-American	0.004%	25,015
South Asian	0.00329%	30,361
Finnishnot grpmax-eligible	0.00157%	63,694

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.Pro1651Ser
Coding: c.4951C>T
MANE Select: NM_001386298
dbSNP: rs201439084
Type: single nucleotide variant
Location: chr19:42290992 (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-pro1651ser (accessed [today's date]).

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